Triazolo[4,5-d]pyrimidine derivatives and their use as purinergic receptor antagonists

ABSTRACT

The use of a compound of formula (I): wherein R 1  is selected from H, alkyl, aryl, alkoxy, aryloxy, alkylthio, arylthio, halogen, CN, NR 5 R 6 , NR 4 CONR 5 , NR 4 CONR 5 R 6 ,NR 4 CO 2 R 7  and NR 4 SO 2 R 7 ; R 2  is selected from aryl attached via an unsaturated carbon; R 3  is selected from H, alkyl, COR 5 , CO 2 R 7 , CONR 5 R 6 , CONR 4 NR 5 R 6  and SO 2 R 7 ; R 4 , R 5  and R 6  are independently selected from H, alkyl and aryl or where R 5  and R 6  are in an NR 5 R 6  group, R 5  and R 6  may be linked to form a heterocyclic group, or where R 4 , R 5  and R 6  are in a (CONR 4 NR 5 R 6 ) group, R 4  and R 5  may be linked to form a heterocyclic group; and R 7  is selected from alkyl and aryl, or a pharmaceutically acceptable salt thereof or prodrug thereof, in the treatment or prevention of a disorder in which the blocking of purine receptors, particularly adenosine receptors and more particularly A 2A  receptors, may be beneficial, particularly wherein said disorder is a movement disorder such as Parkinson&#39;s disease or said disorder is depression, cognitive or memory impairment, acute or chronic pain, ADHD or narcolepsy, or for neuroprotection in a subject; compounds of formula (I) for use in therapy; and novel compounds of formula (I) per se

The present invention relates to triazolo[4,5-d]pyrimidine derivatives and their use in therapy. In particular, the present invention relates to the treatment of disorders in which the reduction of purinergic neurotransmission could be beneficial. The invention relates in particular to the blockade of adenosine receptors and particularly adenosine A_(2A) receptors, and to the treatment of movement disorders such as Parkinson's disease.

Movement disorders constitute a serious health problem, especially amongst the elderly sector of the population. These movement disorders are often the result of brain lesions. Disorders involving the basal ganglia which result in movement disorders include Parkinson's disease, Huntington's chorea and Wilson's disease. Furthermore, dyskinesias often arise as sequelae of cerebral ischaemia and other neurological disorders.

There are four classic symptoms of Parkinson's disease: tremor, rigidity, akinesia and postural changes. The disease is also commonly associated with depression, dementia and overall cognitive decline. Parkinson's disease has a prevalence of 1 per 1,000 of the total population. The incidence increases to 1 per 100 for those aged over 60 years. Degeneration of dopaminergic neurones in the substantia nigra and the subsequent reductions in interstitial concentrations of dopamine in the striatum are critical to the development of Parkinson's disease. Some 80% of cells from the substantia nigra need to be destroyed before the clinical symptoms of Parkinson's disease are manifested.

Current strategies for the treatment of Parkinson's disease are based on transmitter replacement therapy (L-dihydroxyphenylacetic acid (L-DOPA)), inhibition of monoamine oxidase (e.g. Deprenyl®), dopamine receptor agonists (e.g. bromocriptine and apomorphine) and anticholinergics (e.g. benztrophine, orphenadrine). Transmitter replacement therapy in particular does not provide consistent clinical benefit, especially after prolonged treatment when “on-off” symptoms develop, and this treatment has also been associated with involuntary movements of athetosis and chorea, nausea and vomiting. Additionally current therapies do not treat the underlying neurodegenerative disorder resulting in a continuing cognitive decline in patients. Despite new drug approvals, there is still a medical need in terms of improved therapies for movement disorders, especially Parkinson's disease. In particular, effective treatments requiring less frequent dosing, effective treatments which are associated with less severe side-effects, and effective treatments which control or reverse the underlying neurodegenerative disorder, are required.

Blockade of A₂ adenosine receptors has recently been implicated in the treatment of movement disorders such as Parkinson's disease (Richardson, P. J. et al., Trends Pharmacol. Sci. 1997, 18, 338–344) and in the treatment of cerebral ischaemia (Gao, Y. and Phillis, J. W., Life Sci. 1994, 55, 61–65). The potential utility of adenosine A_(2A) receptor antagonists in the treatment of movement disorders such as Parkinson's Disease has recently been reviewed (Mally, J. and Stone, T. W., CNS Drugs, 1998, 10, 311–320).

Adenosine is a naturally occurring purine nucleoside which has a wide variety of well-documented regulatory functions and physiological effects. The central nervous system (CNS) effects of this endogenous nucleoside have attracted particular attention in drug discovery, owing to the therapeutic potential of purinergic agents in CNS disorders (Jacobson, K. A. et al., J. Med. Chem. 1992, 35, 407–422). This therapeutic potential has resulted in considerable recent research endeavour within the field of adenosine receptor agonists and antagonists (Bhagwhat, S. S.; Williams, M. E. Exp. Opin. Ther. Patents 1995, 5,547–558).

Adenosine receptors represent a subclass (P₁) of the group of purine nucleotide and nucleoside receptors known as purinoreceptors. The main pharmacologically distinct adenosine receptor subtypes are known as A₁, A_(2A), A_(2B) (of high and low affinity) and A₃ (Fredholm, B. B., et al., Pharmacol. Rev. 1994, 46, 143–156). The adenosine receptors are present in the CNS (Fredholm, B. B., News Physiol. Sci., 1995, 10, 122–128).

The design of P₁ receptor-mediated agents has been reviewed (Jacobson, K. A., Suzuki, F., Drug Dev. Res., 1997, 39, 289–300; Baraldi, P. G. et al., Curr. Med. Chem. 1995, 2, 707–722), and such compounds are claimed to be useful in the treatment of cerebral ischemia or neurodegenerative disorders, such as Parkinson's disease (Williams, M. and Burnstock, G. Purinergic Approaches Exp. Ther. (1997), 3–26. Editor. Jacobson, Kenneth A.; Jarvis, Michael F. Publisher: Wiley-Liss, New York, N.Y.)

It has been speculated that xanthine derivatives such as caffeine may offer a form of treatment for attention-deficit hyperactivity disorder (ADHD). A number of studies have demonstrated a beneficial effect of caffeine on controlling the symptoms of ADHD (Garfinkel, B. D. et al., Psychiatry, 1981, 26, 395–401). Antagonism of adenosine receptors is thought to account for the majority of the behavioural effects of caffeine in humans and thus blockade of adenosine A_(2A) receptors may account for the observed effects of caffeine in ADSD patients. Therefore a selective A_(2A) receptor antagonist may provide an effective treatment for ADHD but without the unwanted side-effects associated with current therapy.

Adenosine receptors have been recognised to play an important role in regulation of sleep patterns, and indeed adenosine antagonists such as caffeine exert potent stimulant effects and can be used to prolong wakefulness Porkka-Heiskanen, T. et al., Science, 1997, 276, 1265–1268). Recent evidence suggests that a substantial part of the actions of adenosine in regulating sleep is mediated through the adenosine A_(2A) receptor (Satoh, S., et al., Proc. Natl. Acad. Sci., USA, 1996). Thus, a selective A_(2A) receptor antagonist may be of benefit in counteracting excessive sleepiness in sleep disorders such as hypersomnia or narcolepsy.

It has recently been observed that patients with major depression demonstrate a blunted response to adenosine agonist-induced stimulation in platelets, suggesting that a dysregulation of A_(2A) receptor function may occur during depression (Berk, M. et al, 2001, Eur. Neuropsychopharmacol. 11, 183–186). Experimental evidence in animal models has shown that blockade of A_(2A) receptor function confers antidepressant activity (El Yacoubi, M et al. Br. J. Pharmacol. 2001, 134, 68–77). Thus, A_(2A) receptor antagonists may offer a novel therapy for the treatment of major depression and other affective disorders in patients.

The pharmacology of adenosine A_(2A) receptors has been reviewed (Ongini, E.; Fredholm, B. B. Trends Pharmacol. Sci. 1996, 17(10), 364–372). One potential underlying mechanism in the aforementioned treatment of movement disorders by the blockade of A₂ adenosine receptors is the evidence of a functional link between adenosine A_(2A) receptors to dopamine D₂ receptors in the CNS. Some of the early studies (e.g. Ferre, S. et al., Stimulation of high-affinity adenosine A₂ receptors decreases the affinity of dopamine D₂ receptors in rat striatal membranes. Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 7238–41) have been summarised in two more recent articles (Fuxe, K. et al., Adenosine Adenine Nucleotides Mol. Biol. Integr. Physiol., [Proc. Int. Symp.], 5th (1995), 499–507. Editors: Belardinelli, Luiz; Pelleg, Amir. Publisher: Kluwer, Boston, Mass.; Ferre, S. et al., Trends Neurosci. 1997, 20, 482–487).

As a result of these investigations into the functional role of adenosine A_(2A) receptors in the CNS, especially in vivo studies linking A₂ receptors with catalepsy (Ferre et al., Neurosci. Lett. 1991, 130, 162–4; Mandhane, S. N. et al., Eur. J. Pharmacol. 1997, 328, 135–141) investigations have been made into agents which selectively bind to adenosine A_(2A) receptors as potentially effective treatments for Parkinson's disease.

While many of the potential drugs for treatment of Parkinson's disease have shown benefit in the treatment of movement disorders, an advantage of adenosine A_(2A) antagonist therapy is that the underlying neurodegenerative disorder may also be treated. The neuroprotective effect of adenosine A_(2A) antagonists has been reviewed (Ongini, E.; Adami, M.; Ferri, C.; Bertorelli, R., Ann. N.Y. Acad. Sci. 1997, 825(Neuroprotective Agents), 30–48). In particular, compelling recent evidence suggests that blockade of A_(2A) receptor function confers neuroprotection against MPTP-induced neurotoxicity in mice (Chen, J-F., J. Neurosci. 2001, 21, RC143). In addition, several recent studies have shown that consumption of dietary caffeine, a known adenosine A_(2A) receptor antagonist, is associated with a reduced risk of Parkinson's disease in man (Ascherio, A. et al, Ann Neurol., 2001, 50, 56–63; Ross G W, et al., JAMA, 2000, 283, 2674–9). Thus, A_(2A) receptor antagonists may offer a novel treatment for conferring neuroprotection in neurodegenerative diseases such as Parkinson's disease.

Xanthine derivatives have been disclosed as adenosine A₂ receptor antagonists as useful for treating various diseases caused by hyperfunctioning of adenosine A₂ receptors, such as Parkinson's disease (see, for example, EP-A-565377).

One prominent xanthine-derived adenosine A_(2A) selective antagonist is CSC [8-(3-chlorostyryl)caffeine] (Jacobson et al., FEBS Lett., 1993, 323, 141–144).

Theophylline (1,3-dimethylxanthine), a bronchodilator drug which is a mixed antagonist at adenosine A₁ and A_(2A) receptors, has been studied clinically. To determine whether a formulation of this adenosine receptor antagonist would be of value in Parkinson's disease an open trial was conducted on 15 Parkinsonian patients, treated for up to 12 weeks with a slow release oral theophylline preparation (150 mg/day), yielding serum theophylline levels of 4.44 mg/L after one week. The patients exhibited significant improvements in mean objective disability scores and 11 reported moderate or marked subjective improvement (Mally, J., Stone, T. W. J. Pharm. Pharmacol. 1994, 46, 515–517).

KF 17837 [(E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine] is a selective adenosine A_(2A) receptor antagonist which on oral administration significantly ameliorated the cataleptic responses induced by intracerebroventricular administration of an adenosine A_(2A) receptor agonist, CGS 21680. KF 17837 also reduced the catalepsy induced by haloperidol and reserpine. Moreover, KF 17837 potentiated the anticataleptic effects of a subthreshold dose of L-DOPA plus benserazide, suggesting that KF 17837 is a centrally active adenosine A_(2A) receptor antagonist and that the dopaminergic function of the nigrostriatal pathway is potentiated by adenosine A_(2A) receptor antagonists (Kanda, T. et al., Eur. J. Pharmacol. 1994, 256, 263–268). The structure activity relationship (SAR) of KF 17837 has been published (Shimada, J. et al., Bioorg. Med. Chem. Lett. 1997, 7, 2349–2352). Recent data has also been provided on the A_(2A) receptor antagonist KW-6002 (Kuwana, Y et al., Soc. Neurosci. Abstr. 1997, 23, 119.14; and Kanda, T. et al., Ann. Neurol. 1998, 43(4), 507–513).

New non-xanthine structures sharing these pharmacological properties include SCH 58261 and its derivatives (Baraldi, P. G. et al., Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine Derivatives: Potent and Selective A_(2A) Adenosine Antagonists. J. Med. Chem. 1996, 39, 1164–71). SCH 58261 (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c] pyrimidine) is reported as effective in the treatment of movement disorders (Ongini, E. Drug Dev. Res. 1997, 42(2), 63–70) and has been followed up by a later series of compounds (Baraldi, P. G. et al., J. Med. Chem. 1998, 41(12), 2126–2133).

The foregoing discussion indicates that a potentially effective treatment for movement disorders in humans would comprise agents which act as antagonists at adenosine A_(2A) receptors.

It has now been found that triazolo[4,5-d]pyrimidine derivatives, which are structurally unrelated to known adenosine receptor antagonists, exhibit unexpected antagonist binding affinity at adenosine (P₁) receptors, and in particular at the adenosine A_(2A) receptor. Such compounds may therefore be useful for the treatment of disorders in which the blocking of purine receptors, particularly adenosine receptors and more particularly adenosine A_(2A) receptors, may be beneficial. In particular such compounds may be suitable for the treatment of movement disorders, such as disorders of the basal ganglia which result in dyskinesias. Disorders of of particular interest include Parkinson's disease, Alzheimer's disease, spasticity, Huntington's chorea and Wilson's disease.

Such compounds may also be particularly suitable for the treatment of depression, cognitive or memory impairment including Alzheimer's disease, acute or chronic pain, ADSD and narcolepsy, or for neuroprotection.

According to the present invention there is provided the use of a compound of formula (I):

wherein

-   R₁ is selected from H, alkyl, aryl, alkoxy, aryloxy, alkylthio,     arylthio, halogen, CN, NR₅R₆, NR₄COR₅, NR₄CONR₅R₆, NR₄CO₂R₇ and     NR₄SO₂R₇; -   R₂ is selected from aryl attached via an unsaturated carbon;

R₃ is selected from H, alkyl, COR₅, CO₂R₇, CONR₅R₆, CONR₄NR₅R₆ and SO₂R₇;

-   R₄, R₅ and R₆ are independently selected from H, alkyl and aryl or     where R₅ and R₆ are in an NR₅R₆ group, R₅ and R₆ may be linked to     form a heterocyclic group, or where R₄, R₅ and R₆ are in a     (CONR₄NR₅R₆) group, R₄ and R₅ may be linked to form a heterocyclic     group; and -   R₇ is selected from alkyl and aryl,     or a pharmaceutically acceptable salt thereof or prodrug thereof, in     the manufacture of a medicament for the treatment or prevention of a     disorder in which the blocking of purine receptors, particularly     adenosine receptors and more particularly A_(2A) receptors, may be     beneficial.

As used herein, the term “alkyl” means a branched or unbranched, cyclic or acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl) hydrocarbyl radical which may be substituted or unsubstituted. Where cyclic, the alkyl group is preferably C₃ to C₁₂, more preferably C₅ to C₁₀, more preferably C₅, C₆ or C₇. Where acyclic, the alkyl group is preferably C₁ to C₁₀, more preferably C₁ to C₆, more preferably methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, isobutyl or tertiary-butyl) or pentyl (including n-pentyl and iso-pentyl), more preferably methyl. It will be appreciated therefore that the term “alkyl” as used herein includes alkyl (branched or unbranched), alkenyl (branched or unbranched), alkynyl (branched or unbranched), cycloalkyl, cycloalkenyl and cycloalkynyl.

As used herein, the term “lower alkyl” means methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tertiary-butyl).

As used herein, the term “aryl” means an aromatic group, such as phenyl or naphthyl, or a heteroaromatic group containing one or more heteroatom(s), such as pyridyl, pyrrolyl, quinolinyl, furanyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, imidazolyl, pyrimidinyl, indolyl, pyrazinyl and indazolyl.

As used herein, the term “heteroaryl” means an aromatic group containing one or more heteroatom(s) preferably selected from N, O and S, such as pyridyl, pyrrolyl, quinolinyl, furanyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, imidazolyl, pyrimidinyl, indolyl, pyrazinyl and indazolyl.

As used herein, the term “non-aromatic heterocyclyl” means a non-aromatic cyclic group containing one or more heteroatom(s) preferably selected from N, O and S, such as a cyclic amino group (including aziridinyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl) or a cyclic ether (including tetrahydrofuranyl).

As used herein, the term “alkoxy” means alkyl-O—. As used herein, the term “aryloxy” means aryl-O—.

As used herein, the term “halogen” means a fluorine, chlorine, bromine or iodine radical.

As used herein, the term “prodrug” means any pharmaceutically acceptable prodrug of a compound of the present invention.

Where any of R₁ to R₁₄ is selected from alkyl, alkoxy and alkylthio, particularly from alkyl and alkoxy, in accordance with formula (I) as defined above, then that alkyl group, or the alkyl group of the alkoxy or alkylthio group, may be substituted or unsubstituted. Where any of R₁ to R₁₄ is selected from aryl, aryloxy and arylthio, particularly from aryl and aryloxy, in accordance with formula (I) as defined above, then said aryl group, or the aryl group of the aryloxy group, may be substituted or unsubstituted. Where R₅ and R₆, or R₄ and R₅, are linked to form a heterocyclic group, the heterocyclic group may be substituted or unsubstituted. Where substituted, there will generally be 1 to 3 substituents present, preferably 1 substituent. Substituents may include:

-   carbon-containing groups such as     -   alkyl,     -   aryl, (e.g. substituted and unsubstituted phenyl (including         alkylphenyl, alkoxyphenyl and halophenyl),     -   arylalkyl; (e.g. substituted and unsubstituted benzyl); -   halogen atoms and halogen containing groups such as     -   haloalkyl (e.g. trifluoromethyl),     -   haloaryl (e.g. chlorophenyl); -   oxygen containing groups such as     -   alcohols (e.g. hydroxy, hydroxyalkyl, hydroxyaryl,         (aryl)(hydroxy)alkyl),     -   ethers (e.g. alkoxy, aryloxy, alkoxyalkyl, aryloxyalkyl,         alkoxyaryl, aryloxyaryl),     -   aldehydes (e.g. carboxaldehyde),     -   ketones (e.g. alkylcarbonyl, arylcarbonyl, alkylcarbonylalkyl,         alkylcarbonylaryl, arylcarbonylalkyl, arylcarbonylaryl,         arylalkylcarbonyl, arylalkylcarbonylalkyl,         arylalkylcarbonylaryl)     -   acids (e.g. carboxy, carboxyalkyl, carboxyaryl),     -   acid derivatives such as esters         -   (e.g. alkoxycarbonyl, aryloxycarbonyl, alkoxycarbonylalkyl,             aryloxycarbonylalkyl, alkoxycarbonylaryl,             aryloxycarbonylaryl, alkylcarbonyloxy,             alkylcarbonyloxyalkyl), amides         -   (e.g. aminocarbonyl, mono- or di-alkylaminocarbonyl,             cyclicaminocarbonyl, aminocarbonylalkyl, mono- or             di-alkylaminocarbonylakyl, arylaminocarbonyl or             arylalkylaminocarbonyl, alkylcarbonylamino,             arylcarbonylamino or arylalkylcarbonylamino), carbamates         -   (eg. alkoxycarbonylamnino, aryloxycarbonylamino,             arylalkyloxycarbonylamino, aminocarbonyloxy, mono- or             di-alkylaminocarbonyloxy, arylaminocarbonyloxy or             arylalkylaminocarbonyloxy) and ureas         -   (eg. mono- or di-alkylaminocarbonylamino,             arylaminocarbonylamino or arylalkylaminocarbonylamino); -   nitrogen containing groups such as     -   amines (e.g. amino, mono- or dialkylamino, cyclicamino,         arylamino, aminoalkyl, mono- or dialkylaminoalkyl),     -   azides,     -   nitriles (e.g. cyano, cyanoalkyl),     -   nitro,     -   sulfonamides (e.g. aminosulfonyl, mono- or di-alkylamino         sulfonyl, mono- or di-arylaminosulfonyl, alkyl- or aryl-sulfonyl         amino, alkyl- or aryl-sulfonyl(alkyl)amino, alkyl- or         aryl-sulfonyl(aryl)amino); -   sulfur containing groups such as     -   thiols, thioethers, sulfoxides, and sulfones         -   (e.g. alkylthio, alkylsulfinyl, alkylsulfonyl,             alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl,             arylthio, arylsulfinyl, arylsulfonyl, arylthioalkyl,             arylsulfinylalkyl, arylsulfonylalkyl) -   and heterocyclic groups containing one or more, preferably one,     heteroatom,     -   (e.g. thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl,         thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl,         aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl,         imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl,         pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl,         hexahydroazepinyl, piperazinyl, morpholinyl, thianaphthyl,         benzofuranyl, isobenzofuranyl, indolyl, oxyindolyl, isoindolyl,         indazolyl, indolinyl, 7-azaindolyl, benzopyranyl, coumarinyl,         isocoumarinyl, quinolinyl, isoquinolinyl, naphthridinyl,         cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl,         quinoxalinyl, chromenyl, chromanyl, isochromanyl, phthalazinyl         and carbolinyl).

Where any of R₁ to R₁₄ is selected from aryl or from an aryl-containing group such as aryloxy or arylthio, preferred substituent group(s) are selected from halogen, alkyl (substituted or unsubstituted; and where substituted particularly from alkoxyalkyl, hydroxyalkyl, aminoalkyl and haloalkyl), hydroxy, alkoxy, CN, NO₂, amines (including amino, mono- and di-alkylamino), alkoxycarbonyl, aminocarbonyl, carboxamido, sulfonamido, alkoxycarbonylamino and aryl, and particularly from unsubstituted alkyl, substituted alkyl (including alkoxyalkyl and aminoalkyl), halogen and amines.

In one embodiment, where any of R₁ to R₁₄ is directly substituted by an alkyl substituent group, or by an alkyl-containing substituent group (such as alkoxy or alkylcarbonylamino for example), then the alkyl moiety of the substituent group directly attached to any of R₁ to R₁₄ may be further substituted by the substituent groups hereinbefore described and particularly by halogen, hydroxy, alkoxy, CN, amines (including amino, mono- and di-alkyl amino) and aryl.

In a further embodiment, where any of R₁ to R₁₄ is directly substituted by an aryl substitutent group, or by an aryl-containing substituent group (such as aryloxy or arylaminocarbonylamino for example), then the aryl moiety of the substituent group directly attached to any of R₁ to R₁₄ may be further substituted by the substituent groups hereinbefore described and particularly by halogen, alkyl (substituted or unsubstituted; and where substituted particularly from alkoxyalkyl, hydroxyalkyl, aminoalkyl and haloalkyl), hydroxy, alkoxy, CN, NO₂, amines (including amino, mono- and di-alkylamino), alkoxycarbonyl, aminocarbonyl, carboxamido, sulfonamido, alkoxycarbonylamino and aryl. In a further embodiment, said aryl moiety is substituted by halogen, alkyl (including CF₃), hydroxy, alkoxy, CN, amines (including amino, mono- and di-alkyl amino) and NO₂. In a further embodiment, said aryl moiety is substituted by unsubstituted alkyl, substituted alkyl (particularly alkoxyalkyl and aminoalkyl), halogen and amines.

The terms “directly substituted” and “directly attached”, as used herein, mean that the substituent group is bound directly to any of R₁ to R₁₄ without any intervening divalent atoms or groups.

In the compounds of formula (I), R₁ is selected from H, alkyl (including branched and unbranched alkyl, substituted and unsubstituted alkyl, and cyclic and acyclic alkyl), aryl (including heteroaryl), alkoxy, aryloxy, alkylthio, arylthio, halogen, CN, NR₅R₆ (including NH₂), NR₄COR₅, NR₄CONR₅R₆, NR₄CO₂R₇ and NR₄SO₂R₇.

In one embodiment, the compounds of formula (I) are those wherein R₁ is selected from alkyl (including branched and unbranched alkyl, substituted and unsubstituted alkyl, and cyclic and acyclic alkyl), aryl (including heteroaryl), alkoxy, aryloxy, alkylthio, arylthio, halogen, CN, NR₅R₆ (including NH₂), NR₄COR₅, NR₄CONR₅R₆, NR₄CO₂R₇ and NR₄SO₂R₇.

Preferably, R₁ is selected from alkyl (including branched and unbranched alkyl, substituted and unsubstituted alkyl, and cyclic and acyclic alkyl), alkoxy, alkylthio, NR₅R₆ (including NH₂), NR₄COR₅, NR₄CONR₅R₆, NR₄CO₂R₇ and NR₄SO₂R₇, more preferably from NR₅R₆ (including NH₂), NR₄COR₅, NR₄CONR₅R₆, NR₄CO₂R₇ and NR₄SO₂R₇, more preferably from NR₅R₆ (including NH₂) and NR₄COR₅, more preferably from NR₅R₆ (including NH₂) and most preferably from NH₂.

Where R₁ is selected from NR₅R₆, in one embodiment R₅ and R₆ are independently selected from hydrogen, alkyl and aryl, preferably from hydrogen.

Where R₁ is selected from NR₄COR₅, in one embodiment R₄ is hydrogen.

Where R₁ is selected from alkyl, R₁ is preferably C₁₋₆ alkyl, more preferably C₁₋₆ saturated alkyl, and more preferably lower alkyl. In one embodiment, R₁ is selected from substituted alkyl, particularly haloalkyl (including CF₃) and arylalkyl (including heteroarylalkyl), and particularly haloalkyl (including CF₃).

Preferably, R₂ is a heteroaryl group, and preferably a heteroaryl group which is attached to the pyrimidine ring of formula (I) such that at least one heteroatom is adjacent to the unsaturated carbon atom attached to said pyrimidine ring. Preferably, R₂ is an N, O or S-containing heteroaryl group. R₂ may contain one or more heteroatom(s) selected from N, O and S.

In one embodiment, the aryl group of R₂ (including wherein R₂ is a heteroaryl group) is not ortho,ortho-disubstituted. Preferably, the aryl group of R₂ (including wherein R₂ is a heteroaryl group) is not substituted at either ortho position. As used herein, reference to ortho-substitution of the R₂ group means the ortho positions of the R₂ group relative to the point of attachment of R₂ to the pyrimidine moiety of formula (I).

In a preferred embodiment, R₂ is selected from furyl (including 2-furyl), thienyl (including 2-thienyl), pyridyl (including 2-pyridyl), thiazolyl (including 2- and 5-thiazolyl), pyrazolyl (including 3-pyrazolyl), triazolyl (including 4-triazolyl), pyrrolyl (including 2-pyrrolyl) and oxazolyl (including 5-oxazolyl). In a further embodiment, R₂ is selected from 2-furyl, 2-thienyl, 2-thiazolyl, 2-pyridyl, 3-pyrazolyl, 2-pyrrolyl, 4-triazolyl and 5-oxazolyl. In a further preferred embodiment, R₂ is selected from furyl, thienyl, pyridyl, thiazolyl and pyrazolyl, and particularly from 2-furyl, 2-thienyl, 2-thiazolyl, 2-pyridyl and 3-pyrazolyl. In a further embodiment, R₂ is selected from furyl, thienyl and pyridyl, preferably 2-furyl, 2-thienyl and 2-pyridyl. In a particularly preferred embodiment, R₂ is selected from furyl, and preferably from 2-furyl, substituted or unsubstituted.

Where R₂ is other than a heteroaryl group, R₂ is preferably phenyl.

In the compounds of formula (I), R₃ is selected from H, alkyl (including branched and unbranched alkyl, substituted and unsubstituted alkyl, cyclic and acyclic alkyl), COR₅, CO₂R₇, CONR₅R₆, CONR₄NR₅R₆ and SO₂R₇.

Where R₃ is selected from alkyl, R₃ is preferably acyclic alkyl, preferably acyclic C₁₋₆ alkyl (including alkenyl and alkynyl), preferably acyclic C₁₋₆ saturated alkyl, preferably lower alkyl. In one embodiment, R₃ is selected from substituted or unsubstituted methyl, ethyl and propyl (n-propyl or isopropyl) groups.

Where R₃ is selected from alkyl, particularly from saturated acyclic C₁₋₆ alkyl, particularly from lower alkyl and particularly from methyl, ethyl and propyl, it is preferred that R₃ is substituted alkyl. Preferred substituents are aryl (including heteroaryl), cycloalkyl, non-aromatic heterocyclyl, CN, COR₅, CO₂R₅, CONR₅R₆, CONR₄NR₅R₆ and C(═NR₄)NR₅R₆, preferably aryl (including heteroaryl), CONR₅R₆, CO₂R₅ and COR₅ (preferably wherein R₅ is aryl), more preferably aryl (including heteroaryl), CONR₅R₆ and COR₅, more preferably aryl (including heteroaryl) and CONR₅R₆, and most preferably aryl (including heteroaryl).

Where R₃ is selected from arylalkyl (including heteroarylalkyl), the aryl (including heteroaryl) group may be unsubstituted, or substituted as defined in detail below in respect of the group referred to as R₁₁. Preferably, the arylalkyl (including heteroarylalkyl group) is an arylmethyl (including heteroarylmethyl) group. The preferred aryl groups are set out below in detail in respect of the group referred to as Ar.

Where R₃ is selected from CONR₅R₆, R₅ and R₆ are selected from H, alkyl (including substituted alkyl such as arylalkyl (including heteroarylalkyl)) and aryl (including heteroaryl) or R₅ and R₆ may be linked to form a heterocyclic ring. In one embodiment, R₅ and R₆ are selected from unsubstituted alkyl and arylalkyl (including heteroarylalkyl). Said aryl groups may be substituted or unsubstituted. In a preferred embodiment one of R₅ and R₆ is hydrogen. In a further preferred embodiment, R₅ is H and R₆ is selected from arylalkyl (including heteroarylalkyl), preferably arylmethyl (including heteroarylmethyl).

In a preferred embodiment, R₃ is selected from H and substituted alkyl, preferably wherein said alkyl is substituted by aryl (including heteroaryl) or CONR₅R₆, and preferably by aryl (including heteroaryl), and more preferably by substituted aryl (including heteroaryl). In one embodiment, R₃ is selected from (CR₉R₁₀)_(n)R₈ wherein n is 1 to 6 (preferably n is 1, 2 or 3, and preferably n is 1), R₉ and R₁₀ are independently selected from H, alkyl and aryl, and R₈ is selected from aryl (including heteroaryl), cycloalkyl, non-aromatic heterocyclic, CN, COR₅, CO₂R₅, CONR₅R₆, CONR₄NR₅R₆ and C(═NR₄)NR₅R₆, preferably aryl (including heteroaryl), CONR₅R₆, CO₂R₅ and COR₅ (preferably wherein R₅ is aryl), more preferably aryl (including heteroaryl), CONR₅R₆ and CO₂R₅, more preferably aryl (including heteroaryl) and CONR₅R₆, and most preferably aryl (including heteroaryl). Preferably, R₉ and R₁₀ are independently selected from H and alkyl (preferably acyclic saturated C₁₋₆ alkyl, preferably lower alkyl, preferably methyl, ethyl or propyl), more preferably H. Preferably, at least one of R₉ and R₁₀ is hydrogen, and preferably both R₉ and R₁₀ are hydrogen.

Where R₈ is aryl (including heteroaryl), the aryl (including heteroaryl) group may be unsubstituted, or may be substituted as defined in detail below for R₁₁. The preferred aryl groups are set out below in detail in respect of the group referred to as Ar.

Where R₈ is selected from CONR₅R₆, R₅ and R₆ are selected from H, alkyl (including substituted alkyl such as arylalkyl (including heteroarylalkyl)) and aryl (including heteroaryl) or R₅ and R₆ may be linked to form a heterocyclic ring. In one embodiment, one or both of R₅ and R₆ are selected from unsubstituted alkyl and arylalkyl (including heteroarylalkyl). In a further embodiment, at least one of R₅ and R₆ is selected from aryl (including heteroaryl). Said aryl group may be substituted or unsubstituted. In a preferred embodiment, one of R₅ and R₆ is hydrogen.

Where R₈ is selected from COR₅, R₅ is preferably aryl (including heteroaryl).

Where R₈ is selected from CO₂R₅, R₅ is preferably alkyl or aryl.

In a further preferred embodiment, R₃ is selected from H and (CR₉R₁₀)_(n)R₈, more preferably from (CH₂)_(n)R₈, preferably wherein R₈ is selected from aryl (including heteroaryl) and CONR₅R₆, more preferably wherein R₈ is selected from aryl (including heteroaryl), and more preferably wherein R₈ is selected from substituted aryl (including heteroaryl).

In a further embodiment, R₃ is selected from (CR₉R₁₀)_(n)R₁₁ wherein R₉, R₁₀ and n are as defined above and R₁₁ is selected from the group consisting of substituted aryl (including heteroaryl) groups, preferably mono-, di- or tri-substituted aryl (including heteroaryl) groups represented by the formula Ar(R₁₂)_(a)(R₁₃)_(b)(R₁₄)_(c) wherein Ar is an aryl (including heteroaryl) group; wherein R₁₂, R₁₃ and R₁₄ are substituent group(s), the same or different; and wherein a, b and c are 0 or 1 such that a+b+c≧1.

In one embodiment, the group Ar is selected from phenyl. In an alternative embodiment, the group Ar is selected from heteroaryl groups such as those described hereinabove, preferably from mono or bicyclic heteroaryl groups, more preferably from pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, preferably 2-pyridyl), indolyl (including 2-indolyl, 3-indolyl, 4indolyl, 5-indolyl, 6-indolyl and 7-indolyl), furyl (including 2-furyl and 3-furyl, preferably 2-furyl), thienyl (including 2-thienyl and 3-thienyl, preferably 2-thienyl), isoindolyl, indolinyl, isoxazolyl, oxazolyl, thiazolyl, pyrazinyl, pyrimidinyl, quinolinyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, indazolyl, benzodioxolyl and dihydrobenzofuranyl, more preferably from pyridyl (preferably 2-pyridyl), indolyl, furyl (preferably 2-furyl) and thienyl (preferably 2-thienyl), and most preferably from pyridyl (preferably 2-pyridyl), furyl (preferably 2-furyl) and thienyl (preferably 2-thienyl).

In one embodiment, the group Ar is selected from phenyl, pyridyl (preferably 2-pyridyl), furyl (preferably 2-furyl), thienyl (preferably 2-thienyl) and indolyl, and particularly from phenyl, pyridyl (preferably 2-pyridyl), furyl (preferably 2-furyl) and thienyl (preferably 2-thienyl).

The substituent groups R₁₂, R₁₃ and R₁₄ may be selected from any of the substituent groups described herein above.

In a preferred embodiment, R₁₂, R₁₃ and R₁₄ are selected from NR₅R₆ (including NH₂, and NHR₅) alkyl (substituted or unsubstituted; preferably C₁₋₆ acyclic alkyl), alkoxy (including fluoroalkoxy), halogen (including F, Cl, Br and I), NO₂, CN, hydroxy, NHOH, CHO, CONR₅R₆, CO₂R₅, NR₄COR₅ preferably NHCOR₅), NR₄CO₂R₇ (preferably NHCO₂R₇), NR₄SO₂R₇ (preferably NHSO₂R₇), OCO₂R₇ and aryl (including heteroaryl).

In a more preferred embodiment, R₁₂, R₁₃ and R₁₄ are selected from NR₅R₆ (including NH₂ and NHR₅), alkyl (substituted or unsubstituted; and preferably C₁₋₆ acyclic saturated alkyl) and halogen (preferably F or Cl, particularly F).

In a particularly preferred embodiment, R₁₂, R₁₃ and R₁₄ are selected from NR₅R₆ (including NH₂ and NHR₅, preferably NH₂) and alkyl (substituted or unsubstituted; preferably C₁₋₆ acyclic saturated alkyl).

Where R₁₂, R₁₃ and R₁₄ are selected from substituted alkyl, said alkyl is preferably selected from alkoxyalkyl, hydroxyalkyl, aminoalkyl (including NH₂-alkyl, mono-alkylaminoalkyl and di-alkylaminoalkyl), haloalkyl (particularly fluoroalkyl (including CF₃)), cyanoalkyl, alkylthioalkyl, alkylcarboxyaminoalkyl, alkoxycarbonylaminoalkyl and alkylsulfonylamino, more preferably from alkoxyalkyl, hydroxyalkyl, aminoalkyl and haloalkyl (particularly fluoroalkyl (including CF₃)) and most preferably from alkoxyalkyl and aminoalkyl.

In one embodiment, the substituent groups R₁₂, R₁₃ and R₁₄ are selected from halogen, alkyl (including CF₃), hydroxy, alkoxy, alkylthio, CN, amines (including amino, mono- and di-alkyl amino) and NO₂.

Where the Ar group is phenyl, the phenyl ring may be mono-, di- or tri-substituted, preferably wherein the substituent group is selected from NR₅R₆, alkyl, alkoxy, halogen, NO₂, CN, hydroxy, CONR₅R₆, CO₂R₅, NR₄COR₅, NR₄CO₂R₇, NR₄SO₂R₇ and OCO₂R₇, as described above, and more preferably from NR₅R₆ (including NH₂ and NHR₅, and preferably NH₂), alkyl (substituted or unsubstituted; preferably C₁₋₆ acyclic saturated alkyl; and, where substituted, preferably from alkoxyalkyl, hydroxyalkyl, aminoalkyl and haloalkyl (particularly fluoroalkyl (including CF₃)), and more preferably from alkoxyalkyl and aminoalkyl) and halogen (preferably F or Cl, particularly F). Where (a+b+c) is 2 or 3, it is preferred that at least one of the substituent groups is NR₅R₆, particularly NH₂.

Where the Ar group is pyridyl, the pyridyl group (which is preferably a 2-pyridyl group) is preferably mono-substituted, preferably 6-substituted. The preferred substituent group(s) are selected from alkyl (including substituted and unsubstituted, saturated and unsaturated (such as alkenyl, including vinyl); and preferably C₁₋₆ acyclic alkyl), alkoxy, halogen, aryl, NO₂, NHOH and CHO, as described above, and more preferably from alkyl (substituted or unsubstituted; preferably C₁₋₆ acyclic saturated alkyl; and, where substituted, preferably from alkoxyalkyl, hydroxyalkyl, aminoalkyl and haloalkyl (particularly fluoroalkyl (including CF₃)), and more preferably from alkoxyalkyl and aminoalkyl).

In a preferred embodiment R₃ is selected from CHR₉R₁₁ wherein R₉ and R₁₁ are as defined above, and preferably wherein Ar is substituted pyridyl or substituted phenyl. Where Ar is substituted phenyl, preferably at least one of R₁₂ and R₁₃, or at least one of R₁₂, R₁₃ and R₁₄, is NR₅R₆, preferably NH₂.

In the compounds of formula (I), R₄, R₅ and R₆ are independently selected from H, alkyl (including branched and unbranched alkyl, substituted and unsubstituted alkyl, cyclic and acyclic alkyl) and aryl (including heteroaryl) or where R₅ and R₆ are in any NR₅R₆ group, R₅ and R₆ may be linked to form a heterocyclic ring, or where R₄, R₅ and R₆ are in a (CONR₄NR₅R₆) group, R₄ and R₅ may be linked to form a heterocyclic ring.

In the compounds of formula (I), R₇ is selected from alkyl (including branched and unbranched alkyl, substituted and unsubstituted alkyl, cyclic and acyclic alkyl) and aryl (including heteroaryl).

Where R₄ to R₇ are independently selected from alkyl, preferably R₄ to R₇ are selected from C₁₋₆ alkyl, preferably C₁₋₆ saturated alkyl and more preferably from lower alkyl.

Where R₅ and R₆, or R₄ and R₅, are linked to form a heterocyclic ring said heterocyclic ring may be saturated, partially unsaturated or aromatic, and is preferably saturated.

Said heterocyclic ring is preferably a 5, 6 or 7-membered ring, preferably a 5 or 6-membered ring, and may contain one or more further heteroatom(s) preferably selected from N, O and S.

In a preferred embodiment, R₁ is NH₂, R₂ is 2-furyl and R₃ is arylmethyl (including heteroarylmethyl).

In one embodiment of the invention, the compounds of formula (I) are selected from those set out in claim 41.

In a further embodiment of the invention, the compounds of formula (I) are selected from those set out in claim 42.

Where chiral the compounds of formula (I) may be in the form of a racemic mixture of pairs of enantiomers or in enantiomerically pure form.

According to a further aspect of the present invention there is provided a method of treating or preventing a disorder in which the blocking of purine receptors, particularly adenosine receptors and more particularly adenosine A_(2A) receptors, may be beneficial, the method comprising administration to a subject in need of such treatment an effective dose of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof.

The disorder may be caused by the hyperfunctioning of the purine receptors.

The disorders of particular interest are those in which the blocking of purine receptors, partiucularly adenosine receptors and more particularly adenosine A_(2A) receptors, may be beneficial. These may include movement disorders such as Parkinson's disease, drug-induced Parkinsonism, post-encephalitic Parkinsonism, Parkinsonism induced by poisoning (for example MPTP, manganese, carbon monoxide) and post-traumatic Parkinson's disease (punch-drunk syndrome).

Other movement disorders in which the blocking of purine receptors, may be of benefit include progressive supernuclear palsy, Huntingtons disease, multiple system atrophy, corticobasal degeneration, Wilsons disease, Hallerrorden-Spatz disease, progressive pallidal atrophy, Dopa-responsive dystonia-Parkinsonism, spasticity or other disorders of the basal ganglia which result in abnormal movement or posture. The present invention may also be effective in treating Parkinson's with on-off phenomena; Parkinson's with freezing (end of dose deterioration); and Parkinson's with prominent dyskinesias.

The compounds of formula (I) may be used or administered in combination with one or more additional drugs useful in the treatment of movement disorders, such as L-DOPA or a dopamine agonist, the components being in the same formulation or in separate formulations for administration simultaneously or sequentially.

Other disorders in which the blocking of purine receptors, particularly adenosine receptors and more particularly adenosine A_(2A) receptors may be beneficial include acute and chronic pain; for example neuropathic pain, cancer pain, trigeminal neuralgia, migraine and other conditions associated with cephalic pain, primary and secondary hyperalgesia, inflammatory pain, nociceptive pain, tabes dorsalis, phantom limb pain, spinal cord injury pain, central pain, post-herpetic pain and HIV pain; affective disorders including mood disorders such as bipolar disorder, seasonal affective disorder, depression, manic depression, atypical depression and monodepressive disease; central and peripheral nervous system degenerative disorders including corticobasal degeneration, demyelinating disease (multiple sclerosis, disseminated sclerosis), Freidrich's ataxia, motoneurone disease (amyotrophic lateral sclerosis, progressive bulbar atrophy), multiple system atrophy, myelopathy, radiculopathy, peripheral neuropathy (diabetic neuropathy, tabes dorsalis, drug-induced neuropathy, vitamin deficiency), systemic lupus erythamatosis, granulomatous disease, olivo-ponto-cerebellar atrophy, progressive pallidal atrophy, progressive supranuclear palsy, spasticity; schizophrenia and related pyshoses; cognitive disorders including dementia, Alzheimers Disease, Frontotemporal dementia, multi-infarct dementia, AIDS dementia, dementia associated with Huntingtons Disease, Lewy body dementia, senile dementia, age-related memory impairment, cognitive impairment associated with dementia, Korsakoff syndrome, dementia pugilans; attention disorders such as attention-deficit hyperactivity disorder (ADHD), attention deficit disorder, minimal brain dysfunction, brain-injured child syndrome, hyperkinetic reaction childhood, and hyperactive child syndrome; central nervous system injury including traumatic brain injury, neurosurgery (surgical trauma), neuroprotection for head injury, raised intracranial pressure, cerebral oedema, hydrocephalus, spinal cord injury; cerebral ischaemia including transient ischaemic attack, stroke (thrombotic stroke, ischaemic stroke, embolic stroke, haemorrhagic stroke, lacunar stroke) subarachnoid haemorrhage, cerebral vasospasm, neuroprotection for stroke, peri-natal asphyxia, drowning, cardiac arrest, subdural haematoma; myocardial ischaemia; muscle ischaemia; sleep disorders such as hypersomnia and narcolepsy; eye disorders such as retinal ischaemia-reperfusion injury and diabetic neuropathy; cardiovascular disorders such as claudication and hypotension; and diabetes and its complications.

According to a further aspect of the present invention there is provided use of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament for the treatment or prevention of movement disorders in a subject.

According to a further aspect of the invention there is provided a method of treating or preventing movement disorders comprising administration to a subject in need of such treatment an effective dose of a compound of formula (I) invention or a pharmaceutically acceptable salt or prodrug thereof.

According to a further aspect of the invention there is provided use of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament for neuroprotection in a subject.

According to a further aspect of the invention there is provided a method of neuroprotection comprising administration to a subject in need of such treatment an effective dose of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof.

The medicament for or method of neuroprotection may be of use in the treatment of subjects who are suffering from or at risk from a neurodegenerative disorder, such as a movement disorder.

According to a further aspect of the invention, there is provided for use in therapy a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof.

The present invention may be employed in respect of a human or animal subject, more preferably a mammal, more preferably a human subject.

According to a further aspect of the present invention, there is provided a compound of formula (I), per se, other than compounds wherein R₁ is H and R₃ is selected from methyl, more preferably other than compounds wherein R₁ is H and R₃ is selected from unsubstituted lower alkyl, more preferably other than compounds wherein R₁ is H and R₃ is selected from unsubstituted alkyl, and more preferably other than compounds wherein R₁ is H.

According to a further aspect of the present invention, there is provided a compound of formula (I), per se, other than compounds wherein R₃ is methyl, preferably other than compounds wherein R₃ is unsubstituted lower alkyl and more preferably other than compounds wherein R₃ is unsubstituted alkyl.

According to a further aspect of the invention there is provided a method of preparing the novel compounds of formula (1). Compounds of formula (1) may be prepared according to conventional synthetic methods. For example compounds of formula (1) where R₁ is NH₂ may be synthesised by standard methods such as those illustrated in Reaction Scheme 1.

Compounds of formula (4) where R₃ is alkyl (including arylalkyl, heteroarylalkyl and (CR₉R₁₀)_(n)CO₂R₅) may be prepared from compounds of formula (3) by standard methods such as reaction with an appropriate alkyl halide, or substituted alkyl halide in the presence of a suitable base such as sodium hydride.

Compounds of formula (4) where R₃ is (CR₉R₁₀)_(n)CONR₅R₆ or (CR₉R₁₀)_(n)CONR₄NR₅R₆ may be prepared from compounds of formula (4) where R₃ is (CR₉R₁₀)_(n)CO₂R₅ by standard methods such as direct reaction with an appropriate amine or hydrazine or by initial hydrolysis of the ester group CO₂R₅ to a carboxylic acid followed by reaction with an appropriate amine or hydrazine in the presence of a standard coupling reagent such as DCC.

Compounds of formula (4) where R₃ is (CR₉R₁₀)_(n)C(═NR₄)NR₅R₆ may be prepared from compounds of formula (4) where R₃ is (CR₉R₁₀)_(n)CN by standard methods such as treatment with an appropriate amine in the presence of trimethyl aluminium.

Compounds of formula (4) where R₃ is (CR₉R₁₀)_(n)CN may be prepared from compounds of formula (3) by standard methods such as treatment with an appropriate substituted alkyl halide in the presence of a suitable base such as sodium hydride.

Compounds of formula (4) where R₃ is CONR₅R₆ or CONR₄NR₅R₆ may be prepared from compounds of formula (3) by standard methods such as treatment with an appropriate isocyanate (R₅NCO or R₆NCO) or carbamoyl chloride (R₅R₆NCOCl or R₅R₆NR₄NCOCl).

Compounds of formula (4) where R₃ is COR₅, CO₂R₇ or SO₂R₇ may be prepared from compounds of formula (3) by standard methods such as treatment with an appropriate acid chloride (R₅COCl), chloroformate (ClCO₂R₇) or sulphonyl chloride (R₇SO₂Cl) in the presence of a suitable base such as triethylamine.

Compounds of formula (3) may be prepared from the known chloro compound of formula (2) by standard methods such as aryl or heteroaryl coupling reactions. Suitable aryl or heteroaryl coupling reactions would include reaction with an appropriate aryl or heteroarylboronic acid derivative, an aryl or heteroaryl trialkylstannane derivative or an aryl or heteroarylzinc halide derivative in the presence of a suitable catalyst such as a palladium complex.

Compounds of formula (3) may also be prepared from compounds of formula (7) by standard methods such as treatment with isoamyl nitrite. Compounds of formula (7) are either known in the literature or may be prepared from compounds of formula (6) by standard methods such as reduction with hydrogen in the presence of a suitable catalyst such as Pd. Compounds of formula (6) are either known in the literature or may be prepared from the known compound of formula (5) by standard methods such as aryl or heteroaryl coupling reactions as described above.

Compounds of formula (1) where R₁ is NR₅R₆ may be prepared from compounds of formula (4) by standard methods such as reductive amination with an appropriate aldehyde or ketone, or by treatment with an appropriate alkyl halide in the presence of a suitable base.

Compounds of formula (1) where R₁ is NR₄CONR₅R₆, wherein R₄ is H, may be prepared from compounds of formula (4) by standard methods such as treatment with an appropriate isocyanate (R₅NCO or R₆NCO) or carbamoyl chloride (R₅R₆NCOCl). Compounds of formula (1) where R₁ is NR₄CONR₅R₆, wherein R₄ is alkyl, may be prepared as described above having first performed an additional alkylation step as described above.

Compounds of formula (1) where R₁ is NR₄COR₅, NR₄CO₂R₇ or NR₄SO₂R₇, wherein R₄ is H, may be prepared from compounds of formula (4) by standard methods such as treatment with an appropriate acid chloride (R₅COCl), chloroformate (ClCO₂R₇) or sulphonyl chloride (R₇SO₂Cl) in the presence of a suitable base. Compounds of formula (1) where R₁ is NR₄COR₅, NR₄CO₂R₇ or NR₄SO₂R₇, wherein R₄ is alkyl may be prepared as described above having first performed an additional alkylation step as described above.

Compounds of formula (1) where R₁ is NH₂ may also be synthesised by standard methods such as those illustrated in Reaction Scheme 2.

Compounds of formula (4) where R₃ is alkyl (including arylalkyl, heteroarylalkyl and (CR₉R₁₀)_(n)CO₂R₅) may be prepared from compounds of formula (10) by standard methods such as aryl or heteroaryl coupling reactions as described above. Compounds of formula (10) where R₃ is alkyl are either known in the literature or may be prepared by methods analogous to those described in the literature. For example compounds of formula (10) where R₃ is alkyl may be prepared from compounds of formula (9) where R₃ is alkyl by standard methods such as treatment with isoamyl nitrite. Compounds of formula (9) where R₃ is alkyl are either known in the literature or may be prepared by methods analogous to those described in the literature such as the treatment of the known compound of formula (8) with an appropriate amine in a suitable solvent preferably at elevated temperature.

Compounds of formula (1) where R₁ is NH₂ may also be synthesised by standard methods such as those illustrated in Reaction Scheme 3.

Compounds of formula (4) where R₃ is alkyl (including arylalkyl, heteroarylalkyl and (CR₉R₁₀)_(n)CO₂R₅) may be prepared from compounds of formula (15) where R₃ is alkyl by standard methods such as treatment with isoamyl nitrite. Compounds of formula (15) where R₃ is alkyl may be prepared from compounds of formula (14) where R₃ is alkyl by standard methods such as reduction with hydrogen in the presence of a suitable catalyst such as Pd. Compounds of formula (14) where R₃ is alkyl are either known in the literature or may be prepared from compounds of formula (13), where X is a suitable leaving group such as a tosylate or triflate group, by standard methods such as treatment with a suitable amine in the presence of a suitable base such as triethylamine. Compounds of formula (13) where X is a suitable leaving group are either known in the literature or may be prepared from compounds of formula (12) by standard methods such as treatment with tosyl chloride or triflic anhydride in the prence of a suitable base such as triethylamine or 2,6-dimethylpyridine. Compounds of formula (12) are either known in the literature or may be prepared from the known compound of formula (11) by standard methods such as aryl or heteroaryl coupling reactions as described above.

Other compounds of formula (1) may be prepared by standard methods such as those illustrated in Reaction Scheme 4.

Compounds of formula (1) where R₁ is H, alkyl or aryl may be prepared from compounds of formula (16) where R₁ is H, alkyl or aryl by standard methods such as aryl or heteroaryl coupling reactions as described above. Compounds of formula (16) where R₁ is H, alkyl or aryl are either known in the literature or may be prepared by methods analogous to those described in the literature.

Compounds of formula (1) where R₁ is alkoxy, aryloxy, alkylthio, arylthio, CN or NR₅R₆ may be prepared from compounds of formula (1) where R₁ is halogen by standard methods such as nucleophilic displacement using an appropriate nucleophilic reagent such as an alcohol, thiol, cyanide or amine (NR₅R₆) in the presence of a suitable base if required. Compounds of formula (1) where R₁ is halogen may be prepared from compounds of formula (16) where R₁ is halogen as described above. Compounds of formula (16) where R₁ is halogen are either known in the literature or may be prepared by methods analogous to those described in the literature.

Compounds of formula (1) where R₁ is NR₄CONR₅R₆, NR₄COR₅, NR₄CO₂R₇ or NR₄SO₂R₇, wherein R₄ is alkyl or aryl, may be prepared from compounds of formula (1) where R₁ is NR₅R₆, wherein R₅ is H and R₆ is alkyl or aryl, by the methods described above.

In certain cases it may be advantageous to prepare a compound of formula (1) where R₃ is selected to perform the function of a protecting group, for example a suitable protecting group would be a benzyl group or substituted benzyl group such as a 3,4-dimethoxybenzyl group. Compounds of this nature may prepared as described above and the protecting group R₃ may be removed by standard methods such as treatment with, for example, TFA to give a compound of formula (1) where R₃ is H. Compounds of formula (1) where R₃ is H may then be used to prepare other compounds of formula (1), where R₃ is as previously defined, by the methods described above.

In the compounds of formula (1) the groups R₁, R₂ and R₃ may be further substituted as defined above and it will be appreciated by those skilled in the art that suitable substituent groups may be introduced directly according to the methods described above or alternatively may be introduced by further functionalisation of substituent groups which themselves are introduced directly. For example where the group R₁, R₂ or R₃ contains a nitro substituent this may be reduced by standard methods to an amino group. The resulting amino group may then be further transformed by a variety of standard methods known to those skilled in the art to an alternative functional group such as an amide, urea, carbamate, sulphonamide or alkylamine.

According to a further aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula (I) in combination with a pharmaceutically acceptable carrier or excipient and a method of making such a composition comprising combining a compound of formula (I) with a pharmaceutically acceptable carrier or excipient.

The pharmaceutical compositions employed in the present invention comprise a compound of the present invention, or pharmaceutically acceptable salts or prodrugs thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients known to those skilled in the art. The term, “pharmaceutically acceptable salts”, refers to salts prepared from pharmaceutically acceptable non-toxic acids including inorganic acids and organic acids.

Where the compounds of formula (I) are basic, salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, oxalic, p-toluenesulfonic and the like. Particularly preferred are hydrochloric, hydrobromic, phosphoric, and sulfuric acids, and most particularly preferred is the hydrochloride salt.

Any suitable route of administration may be employed for providing the patient with an effective dosage of a compound of the present invention. For example, oral, rectal, parenteral (intravenous, intramuscular), transdermal, subcutaneous, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, patches, and the like. The most suitable route in any given case will depend on the severity of the condition being treated. The most preferred route of administration of the present invention is the oral route. The compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

In practical use, the compounds can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral (e.g. intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavouring agents, preservatives, colouring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used in the case of oral solid preparations such as, for example, powders, capsules, and tablets, with the solid oral preparations being preferred over the liquid preparations. The most preferred solid oral preparation is tablets.

Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are employed. If desired, tablets may be coated by standard aqueous or non-aqueous techniques.

In addition to the common dosage forms set out above, the compounds may also be administered by controlled release means and/or delivery devices such as those described in U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200; 4,008,719; 4,687,660; and 4,769,027, the disclosures of which are hereby incorporated by reference.

Pharmaceutical compositions employed in the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, or aerosol sprays each containing a predetermined amount of the active ingredient as a powder or granules, a solution or a suspension in an aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such compositions may be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.

For example, a tablet may be prepared by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

The invention is further defined by reference to the following examples. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practised without departing from the purpose and interest of this invention.

EXAMPLES Synthetic Examples

The invention is illustrated with reference to the following Examples, as set out in Table 1.

TABLE 1 Example Structure Compound Name 1

7-(2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 2

N,N-bis(2-fluorobenzyl)-3-(2-fluorobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 3

3-(2-fluorobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 4

7-(2-furyl)-3-(3-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 5

3-(3-aminobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 6

methyl 3-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)methylbenzoate 7

3-(3,5-dimethoxybenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 8

3-(5-chloro-2-thienyl)methyl-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 9

N-(3-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)methyl)phenyl-(1-methyl-1H-imidazol-4-yl)sulphonamide 10

5-amino-N-benzyl-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylcarboxamide 11

7-(2-furyl)-3-(3-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 12

7-(2-furyl)-3-(2-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 13

3-(2-aminobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 14

ethyl 5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[45-d]pyrimidin-3-ylacetate 15

3-(3-cyanobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 16

7-(2-furyl)-3-(3-(3-pyridyl)propyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 17

7-(2-furyl)-3-(3-trifluoromethylbenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 18

7-(2-furyl)-3-(3-hydroxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 19

7-(5-methyl-2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 20

3-(2-fluorobenzyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 21

7-(1H-pyrazol-3-yl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 22

3-(2-fluorobenzyl)-7-(5-thiazolyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 23

7-(2-furyl)-3-(3-methylbenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 24

7-(2-furyl)-3-(2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 25

7-(2-furyl)-3-(3-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 26

(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)acetic acid 27

3-(3-chlorobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 28

3-(2-fluorobenzyl)-7-(1H-pyrazol-3-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 29

7-(2-furyl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 30

(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)acetamide 31

(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-N-(3-chlorophenyl)acetamide 32

7-(2-furyl)-3-(6-methoxy-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 33

7-(2-furyl)-3-(2-thienylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 34

3-(2-fluorobenzyl)-7-(2-thiazolyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 35

3-(2-fluorobenzyl)-7-(2-thienyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 36

3-(3-aminobenzyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 37

7-(2-furyl)-3-(6-methyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 38

3-(2-fluorobenzyl)-7-(5-methyl-2-thiazolyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 39

tert-butyl N-(3-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-ylmethyl)benzyl)carbamate 40

3-(2,5-dimethoxybenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 41

3-(2,6-difluorobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 42

3-(2-fluorobenzyl)-7-(4-methyl-2-thiazolyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 43

7-(2-thienyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 44

6-chloro-N-(7-(2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)pyridine-3-carboxamide 45

3-(3-nitrobenzyl)-7-(5-thiazolyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 46

3-(3-aminomethylbenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 47

3-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)-N,N-dimethylbenzamide 48

3-(3-aminobenzyl)-7-(2-thienyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 49

3-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)-N-methylbenzamide 50

3-(3-aminobenzyl)-7-(5-thiazolyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 51

3-(2-fluoro-5-methoxybenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 52

(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-N-(2-pyridyl)acetamide 53

(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-N-(2-pyridylmethyl)acetamide 54

(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-N-phenylacetamide 55

3-(3,5-dinitrobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 56

7-(5-methyl-2-furyl)-3-(3-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 57

3-(2,3-difluorobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 58

3-(2,4-difluorobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 59

7-(5-methyl-2-furyl)-3-(6-methyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 60

3-(2,6-difluorobenzyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 61

7-(5-methyl-2-furyl)-3-(2-thienylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 62

3-(3-chlorobenzyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 63

7-(2-furyl)-3-(4-methoxy-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 64

7-(2-furyl)-3-(2-methylbenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 65

3-(2,5-difluorobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 66

7-(2-furyl)-3-(2-methoxy-5-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 67

3-(5-amino-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)-N-methylbenzamide 68

N-(3-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)benzyl)acetamide 69

3-(2-fluorobenzyl)-7-(5-oxazolyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 70

3-(4-chloro-2-pyridylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 71

3-(6-fluoro-2-pyridylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 72

3-(2-methoxybenzyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 73

tert-butyl N-(3-(5-amino-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-ylmethyl)benzyl)carbamate 74

3-(2-aminobenzyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-aminehydrochloride 75

3-(3,5-diaminobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 76

3-(3-aminomethylbenzyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine hydrochloride 77

7-(2-furyl)-3-(2-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 78

3-(2-fluoro-5-nitrobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 79

3-(5-amino-2-fluorobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 80

3-(2-fluorobenzyl)-7-(1H-triazol-4-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 81

3-(6-chloro-2-pyridylmethyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 82

7-(5-methyl-2-furyl)-3-(6-phenyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 83

3-(3-aminobenzyl)-7-(2-thiazolyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 84

3-(5-amino-2-fluorobenzyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine hydrochloride 85

N-(3-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)benzyl)-3-methylbutanamide 86

7-(5-methyl-2-furyl)-3-(4-nitro-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 87

3-(4-hydroxylamino-2-pyridylmethyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 88

7-(2-furyl)-3-(2-methyl-3-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 89

3-(3-amino-2-methylbenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 90

3-(3-amino-4-methylbenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 91

3-(3,5-dimethylisoxazol-4-ylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 92

7-(2-furyl)-3-(3-methyl-2-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 93

3-cyclohexylmethyl-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 94

7-(2-furyl)-3-(3-methyl-4-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 95

7-(2-furyl)-3-(3-methyl-2-pyridylmethy)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 96

7-(2-furyl)-3-(5-methyl-2-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 97

3-(4-amino-3-methylbenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 98

3-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)benzoic acid 99

3-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)benzamide 100

7-(2-furyl)-3-(2-methylthiazol-4-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 101

3-(3-aminomethylbenzyl)-7-(1H-pyrazol-3-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 102

3-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)-N-isopropyl-N-methylbenzamide 103

3-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)-N-isopropylbenzamide 104

3-(2-amino-5-methylbenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 105

3-(4-cyano-2-pyridylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 106

7-(2-furyl)-3-(5-methyl-2-pyrazinylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 107

7-(2-furyl)-3-(8-quinolinylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 108

7-(2-furyl)-3-(2-phenylthiazol-4-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 109

7-(4-methyl-2-thiazolyl)-3-(3-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 110

3-(4-chloro-3-nitrobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 111

3-[1,2,5-benzoxadiazol-5-yl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 112

7-(2-furyl)-3-(6-methoxymethyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 113

3-benzyl-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 114

3-(3-amino-4-chlorobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 115

7-(2-furyl)-3-(4-nitro-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 116

7-(2-furyl)-3-(4-hydroxylamino-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 117

7-(2-furyl)-3-(6-methyl-4-nitro-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 118

7-(2-furyl)-3-(4-hydroxylamino-6-methyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 119

3-(4-chloro-2-nitrobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 120

3-(2-amino-4-chlorobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 121

3-(4-cyanobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 122

3-(3,4-dimethoxybenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-aminetrifluoroacetate salt 123

7-(5-methyl-2-furyl)-3-(3-methyl-4-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 124

3-(4-amino-3-methylbenzyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 125

7-(2-furyl)-3-(5-methyl-3-oxazolyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 126

7-(2-furyl)-3-(3-methyl-4-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 127

3-(1,2,5-benzothiadiazol-4-ylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 128

7-(2-furyl)-3-(2-pyrazinylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 129

3-(4-fluoro-3-nitrobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 130

3-(3-nitrobenzyl)-7-phenyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 131

7-(2-furyl)-3-(4-methyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 132

tert-butyl N-(2-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-ylmethyl)-4-pyridylmethyl)carbamate 133

7-(2-furyl)-3-(3-methoxy-4-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 134

7-(2-furyl)-3-(4-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 135

3-(6-ethyl-2-pyridylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 136

3-(2-ethyl-4-pyridylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 137

tert-butyl 7-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-ylmethyl)indole-1-carboxylate 138

tert-butyl 4-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-ylmethyl)indole-1-carboxylate 139

7-(2-furyl)-3-(4-indolylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 140

tert-butyl N-(4-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-ylmethyl)benzyl)carbamate 141

3-(4-aminobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 142

tert-butyl 5-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-ylmethyl)indole-1-carboxylate 143

tert-butyl N-(4-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-ylmethyl)-2-fluorophenyl)carbamate 144

3-(4-aminomethylbenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 145

7-(5-ethyl-2-furyl)-3-(3-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 146

tert-butyl 6-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-ylmethyl)indole-1-carboxylate 147

3-(4-amino-3-fluorobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 148

tert-butyl (4-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-ylmethyl)-3,5-difluorophenyl)carbonate 149

3-(2,6-difluoro-4-hydroxybenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 150

3-(3-aminobenzyl)-7-(5-ethyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 151

3-(3-aminobenzyl)-7-phenyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 152

7-(2-furyl)-3-(6-indolylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 153

7-(2-furyl)-3-(5-indolylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 154

7-(2-furyl)-3-(7-indolylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 155

3-(5-fluoro-2-nitrobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 156

3-(2,6-difluoro-4-methoxybenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 157

tert-butyl N-(2-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-ylmethyl)benzyl)carbamate 158

3-(1H-benzothiazol-5-ylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 159

7-(2-furyl)-3-(2-methoxy-4-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 160

N-(3-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-ylmethyl)phenylacetamide 161

3-(2-aminomethylbenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 162

3-(3-(N,N-dimethylamino)benzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 163

3-(4-difluoromethoxybenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 164

7-(2-furyl)-3-(6-phthalimidomethyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 165

3-(3-amino-4-fluorobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 166

3-(2,3-dihydrobenzofuran-5-ylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 167

3-(5-bromo-2-fluorobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 168

7-(2-furyl)-3-(2,3,5-trifluorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 169

3-(2-fluoro-5-iodobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 170

7-(2-furyl)-3-(2-furylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 171

3-(2-amino-5-fluorobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 172

tert-butyl (5-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-ylmethyl)-2-nitrophenyl)carbonate 173

3-(4-amino-3-hydroxybenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 174

3-(4-amino-3-fluorobenzyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 175

3-(3-aminobenzyl)-7-(1H-pyrazol-3-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 176

7-(2-furyl)-3-(3-hydroxy-4-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 177

N-(6-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)-2-pyridylmethyl)acetamide 178

N-(2-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)benzyl)acetamide 179

7-(2-furyl)-3-(3-thienylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 180

3-(3-amino-2-methylbenzyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 181

7-(2-furyl)-3-(3-methyl-2-thienyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 182

3-(6-allyloxymethyl-2-pyridylmethyl)-N,N-diallyl-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 183

3-(6-methoxymethyl-2-pyridylmethyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 184

3-(4-aminobenzyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 185

3-(6-allyloxymethyl-2-pyridylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 186

3-(6-allyloxymethyl-2-pyridylmethyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 187

7-(2-furyl)-3-(3-isopropyl-4-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 188

7-(2-furyl)-3-(quinolin-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 189

7-(2-furyl)-3-(4-(N-methylamino)benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 190

2-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-1-(6-methyl-2-pyridyl)propanone 191

3-(3-aminobenzyl)-7-(1H-pyrrol-2-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 192

3-(3-nitrobenzyl)-7-(2-pyridyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 193

N-(4-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)phenyl)acetamide 194

7-(2-furyl)-3-(4-nitro-2-(2-trimethylsilylethoxy)methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 195

3-(3-ethyl-4-nitrobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 196

7-(2-furyl)-3-(2-(2-thienylethyl))-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 197

7-(2-furyl)-3-(6-isopropyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 198

7-(2-furyl)-3-(1-(2H-tetrahyropyran-2-yl)indazol-5-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 199

3-(4,6-diisopropyl-2-pyridylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 200

7-(2-furyl)-3-(5-indazolylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 201

7-(2-furyl)-3-(2-hydroxy-4-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 202

7-(2-furyl)-3-(6-vinyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 203

tert-butyl 5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-carboxylate 204

tert-butyl 3-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-ylmethyl)indole-1-carboxylate 205

6-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)pyridine-2-carboxaldehyde 206

tert-butyl 2-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-ylmethyl)indole-1-carboxylate 207

3-(2-indolylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 208

3-(5-ethyl-2-thienylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 209

7-(2-furyl)-3-(3,4-methylenedioxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 210

3-(4-amino-3-ethylbenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 211

2-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-1-phenylethanone 212

N-(3-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-methyl)phenyl)thiophene-2-carboxamide 213

7-(2-furyl)-3-(6-hydroxymethyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine hydrochloride 214

N-(3-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-methyl)phenyl)-3,3-dimethylbutanamide 215

N-(3-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-methyl)phenyl)cyclopropanecarboxamide 216

7-(2-furyl)-3-(6-n-propyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 217

7-(2-furyl)-3-(6-isobutyloxymethyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 218

3-(6-bromomethyl-2-pyridylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 219

3-(4-amino-3-isopropylbenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 220

3-(6-cyanomethyl-2-pyridylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 221

3-(4-hydroxybenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 222

2-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-1-(4-nitrophenyl)ethanone 223

4-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylacetyl)-benzonitrile 224

N-(3-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)phenyl)propanesulphonamide 225

N-(3-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)phenyl)-5-chloro-2-thiophenesulphonamide 226

7-(2-furyl)-3-(6-(N-methylamino)methyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine hydrochloride 227

2-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-1-(4-(N,N-diethylamino)phenyl)ethanone 228

7-(2-furyl)-3-(6-isopropyl-3-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 229

2-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-1-(4-methoxyphenyl)ethanone 230

tert-butyl 7-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-ylmethyl)-5-chloroindole-1-carboxylate 231

3-(5-chloro-7-indolyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 232

N-(3-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)phenyl)-3,5-dimethylisoxazol-4-ylsulphonamide 233

3-(6-(N,N-dimethylamino)methyl-2-pyridylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 234

7-(2-furyl)-3-(6-methylthiomethyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 235

2-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-1-(2-nitrophenyl)ethanone 236

N-(3-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)phenyl)-1,2-dimethyl-1H-imidazol-4-ylsulphonamide 237

N,N-bis(6-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)-2-pyridylmethyl)methanesulphonamide 238

7-(2-furyl)-3-(6-methylsulphonylmethyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 239

N-(6-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)-2-pyridylmethyl)-N-methyl methanesulphonamide 240

3-(3-aminobenzyl)-7-(4,5-dimethyl-2-thiazolyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 241

3-(4-amino-2-fluorobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 242

2-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-1-indanone 243

7-(2-furyl)-3-(5-methyl-7-indolylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 244

N-(4-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)-2-methylphenyl)formamide 245

2-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-1-phenylpropanone 246

3-(7-fluoro-5-indolyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 247

7-(2-furyl)-3-(6-isopropoxymethyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 248

3-(6-ethyl-2-pyridylmethyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 249

3-(4-chloro-5-indolyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 250

3-(7-bromo-5-indolyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 251

3-(6-chloro-5-indolyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 252

3-(3-(4-fluorobenzylamino)benzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 253

3-(6-ethoxy-2-pyridylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 254

3-(6-ethoxy-2-pyridylmethyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 255

3-(3-(2-pyridylmethylamino)benzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 256

7-(2-furyl)-3-(1-(4-trifluoromethylphenyl)ethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 257

3-(6-fluoro-5-indolyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 258

3-(5-fluoro-2-indolyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 259

3-(3,5-dimethyl-4-nitrobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 260

3-(1-(3-fluorophenyl)ethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 261

3-(7-chloro-5-indolyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 262

3-(4-amino-3,5-dimethylbenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 263

3-(1-(3-aminophenyl)ethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 264

7-(2-furyl)-3-(6-(2-methoxyethyl)-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 265

7-(2-furyl)-3-(1-(5,6-dimethyl-2-pyridyl)propyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 266

3-(3-nitrobenzyl)-7-(1H-pyrazol-3-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-aminehydrochloride 267

7-(5-methyl-2-furyl)-3-(2-methyl-3-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 268

7-(5-methyl-2-furyl)-3-(4-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 269

tert-butyl N-(4-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-ylmethyl)phenyl)-N-methylcarbamate 270

tert-butyl 2-(5-amino-3-(3-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)pyrrole-1-carboxylate 271

7-(4,5-dimethylthiazol-2-yl)-3-(3-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 272

3-(2-fluoro-4-nitrobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 273

tert-butyl 7-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-ylmethyl)-5-methylindole-1-carboxylate 274

ethyl N-(4-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)methyl)-2-methylphenyl)carbamate

The general synthetic methods used for the preparation of these Examples are set out below as Methods A to BH. Table 2 sets out the Method used for each Example, together with analytical data.

HPLC is carried out using the following conditions: Column. Waters Xterra RP 18 (50×4.6 mm); Particle size 5 μM; Mobile phase MeOH: 10 mM aq NH₄OAc (pH 7 buffer); Gradient 50:50 isocratic for 1 min. then linear gradient 50:50 to 80:20 over 5 min. then 80:20 isocratic for 3 min.; Flow rate 2.0 mL/min.; Detection wavelength λ=230 nM. Retention times are provided.

Method A

7-(2-Furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine Example 1

A solution of 7-chloro-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (570 mg, 3.34 mmol) in N-methyl-2-pyrrolidinone (4 mL) was treated with PdCl₂(PPh₃)₂ (117 mg, 0.17 mmol) and 2-(tributylstannyl)furan (1.05 mL, 1 mmol), stirred at 80° C. for 5 h, diluted with EtOAc, filtered through a silica pad and concentrated in vacuo. The residue was triturated with diethyl ether and the title compound isolated as a yellow solid (438 mg, 65%).

Method B

3-(2-Fluorobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine Example 3

A solution of 7-(2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (101 mg, 0.5 mmol) in DMF (2 mL), at 0° C., was treated with NaH (20 mg, 60%, 0.5 mmol), stirred for 20 mins then treated with 2-fluorobenzyl bromide (60 μL, 0.5 mmol). The reaction mixture was allowed to warm to room temperature, stirred for 1 h, quenched with water, extracted with EtOAc, dried (MgSO₄) and concentrated in vacuo. The crude product was purified by chromatography (EtOAc:Heptane, 1:4-EtOAc:Heptane, 2:1) to give N,N-bis(2-fluorobenzyl)-3-(2-fluorobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (Example 2) (28 mg, 11%) as a yellow solid and the title compound (34 mg, 22%) as a yellow solid.

Method C

3-(3-Aminobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine Example 5

A solution of 7-(2-furyl)-3-(3-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (152 mg, 0.45 mmol) in EtOH (2 mL) at 50° C. was treated with a solution of SnCl₂ (305 mg, 1.35 mmol) in conc. HCl (0.7 mL), stirred for 2 h, cooled, diluted with water, basified to pH 10 (5-M, NaOH) and filtered to give the title compound (127 mg, 92%) as a white solid.

Method D

N-(3-(5-Amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)methyl)phenyl-(1-methyl-1H-imidazol-4-yl)sulphanamide Example 9

A solution of 3-(3-aminobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (125 mg, 0.41 mmol) in DMF (2 mL) was treated with Et₃N (85 μL, 0.61 mmol) and 1-methylimidazole-4-sulphonyl chloride (74 mg, 0.41 mmol), stirred at room temperature overnight, poured into water, extracted with EtOAc, dried (MgSO₄) and concentrated in vacuo. The crude product was purified by chromatography [SiO₂; EtOAc:MeOH (1:10)] to give the title compound (26 mg, 14%) as a cream solid.

Method E

5-Amino-N-benzyl-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylcarboxamide Example 10

A solution of 7-(2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (202 mg, 1.0 mmol) in DMF (3 mL) was treated with benzyl isocyanate (123 μL, 1.0 mmol) and a catalytic amount of DMAP, stirred at room temperature overnight, diluted with EtOAc and filtered to give the tide compound (62 mg, 19%) as a peach coloured solid.

Method F

Ethyl 5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylacetate Example 14

A solution of 7-(2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (101 mg, 0.5 mmol) in DMF (4 mL) was treated with 4-(N,N-dimethylamino)pyridine (5 mg, 0.04 mmol) and ethyl bromoacetate (55 μL, 0.5 mmol), stirred at room temperature for 16 h and purified directly by chromatography [SiO₂; EtOAc:Heptane (1:2)] to give the title compound (50 mg, 35%) as a white solid.

Method G

7-(2-Furyl)-3-(3-hydroxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine5-amine Example 18

A solution of 7-(2-furyl)-3-(3-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (119 mg, 0.37 mmol) in dichloromethane (20 mL) at 0° C. was treated with boron tribromide (1-M in dichloromethane, 8.8 mL, 8.8 mmol) portion-wise over 3 days, concentrated in vacuo and isolated by filtration to give the title compound (114 mg, 100%) as a yellow solid.

Method H

6-(5-Methyl-2-furyl)-5-nitropyrimidine-2,4-diamine

A solution of 6-chloro-5-nitropyrimidine-2,4-diamine (10 g, 60% pure, 32 mmol) in THF (300 mL) was treated with saturated aq NaHCO₃ (75 mL), 5-methylfuran-2-boronic acid (7.33 g, 0.058 mol) and Pd(PPh₃)₄ (1 g, 0.865 mmol) and refluxed with vigorous stirring under argon overnight. The mixture was cooled to room temperature, diluted with EtOAc (400 mL) and water (300 mL), filtered to remove insoluble material and the filtrate was extracted with EtOAc (2×100 mL). The combined organic phase was dried (MgSO₄), concentrated in vacuo and the resulting solid triturated with dichloromethane and filtered to give the title compound (6 g, 72%) as a yellow solid; mp 196.3–196.9° C.; IR ν_(max) (Nujol)/cm⁻¹ 3442, 3169, 2930, 1629, 1463, 1377, 1027, and 790; NMR δ_(H) (400 MHz, DMSO) 7.40 (2H, br s), 7.09 (2H, br s), 6.87 (1H, dd, J 0.5, 3.2 Hz), 6.26 (2H, dd, J 1.0, 3.3 Hz) and 2.28 (3H, s).

Method I

6-(5-Methyl-2-furyl)pyrimidine-2,4,5-triamine

A suspension of 6-(5-methyl-2-furyl)-5-nitropyrimidine-2,4-diamine (6.6 g, 29.6 mmol) and 10% Pd/C (0.66 g) in MeOH (100 mL) was heated at 40° C. under an atmosphere of H₂ for 3 h, cooled to room temperature, filtered through Celite, and concentrated in vacuo to give the title compound (5.8 g, 99%) as an off-white solid; IR ν_(max) (DR)/cm⁻¹ 3333, 2237, 1634, 1458, 1237, 1025, 963 and 828; NMR δ_(H) (400 MHz, DMSO) 6.77 (1H, dd, J 0.5, 3.2 Hz), 6.21–6.17 (3H, m), 5.14 (2H, s), 4.21 (2H, s), and 2.35 (3H, s).

Method J

7-(5-Methyl-2-furyl)-1H-[1,2,3]triazolo[4,5-d]primidine-5-amine Example 19

A solution of 6-(5-methyl-2-furyl)pyrimidine-2,4,5-triamine (5.8 g, 30.1 mmol) in dioxane (116 mL) was treated with isoamyl nitrite (4.1 mL, 30.5 mmol), heated at 80° C. for 3.5 h, cooled to room temperature and the resulting precipitate was filtered, washed with dioxane (10 mL) and heptane (2×15 mL) then triturated with heptane and filtered to give the title compound (4.7 g, 77%) as a sandy solid.

Method K

7-(1H-Pyrazol-3-yl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine Example 21

A solution of 7-(1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrazol-3-yl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (120 mg, 0.361 mmol) in MeOH (2 mL) was treated with HC1 (4-M in dioxan, 1 mL), stirred for 2 h, filtered and the resulting solid washed with Et₂O to give the title compound (76 mg, 100%) as a yellow solid.

Method L

(2-Amino-6-(2-furyl)-5-nitropyrimidin-4-yl) 4-methylbenzenesulphonate

A suspension of 2-amino-6-(2-furyl)-5-nitropyrimidine-4(1H)-one (1.00 g, 4.50 mmol) in dichloromethane (50 mL) was treated with triethylamine (0.941 mL, 6.75 mmol) and p-toluenesulfonyl chloride (944 mg, 4.95 mmol), stirred for 1 h, diluted with dichloromethane (50 mL), washed with 2-M HCl (20 mL), dried (MgSO₄), concentrated in vacuo and purified by chromatography [SiO₂; isohexane:EtOAc (2:1)] to give the title compound (410 mg, 24%) as a yellow solid; NMR δ_(H) (400 MHz, CDCl₃) 7.95 (2H, d, J 8.5 Hz), 7.59–7.57 (1H, m), 7.39 (2H, d, J 8.5 Hz), 7.23–7.21 (1H, m), 6.59–6.51 (1H, m), 5.39 (2H, br s), 2.48 (3H, s); Retention time 5.68 min.

Method M

6-(2-Furyl)-5-nitro-N⁴-(2-pyridylmethyl)pyrimidine-2,4-diamine

A solution of (2-amino-6-(2-furyl)-5-nitropyrimidin-4-yl) 4-methylbenzenesulphonate (478 mg, 1.27 mmol) in dimethoxyethane (15 mL) was treated with triethylamine (0.531 mL, 3.81 mmol) and 2-pyridinemethylamine (0.393 mL, 3.81 mmol), stirred for 16 h, poured into water (100 mL) and the resulting solid was filtered to give the title compound (275 mg, 69%) as a yellow solid; NMR δ_(H) (400 MHz, CDCl₃) 8.70–8.58 (2H, m), 7.70–7.66 (1H, m), 7.55–7.54 (1H, m), 7.28 (1H, d, J 8.0 Hz), 7.24–7.20 (1H, m), 7.07–7.06 (1H, m), 6.54–6.52 (1H, m), 5.26 (2H, br s) and 4.83 (2H, d, J 5.0 Hz); Retention time 1.44 min.

Method N

7-(2-Furyl)-3-(2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine Example 24

A solution of 6-(2-furyl)-5-nitro-N⁴-(2-pyridylmethyl)pyrimidine-2,4-diamine (270 mg, 0.864 mmol) and 10% Pd/C (92 mg, 0.086 mmol) in EtOH (30 mL) and EtOAc (10 mL) was stirred under an hydrogen atmosphere for 1 h, filtered through Celite and concentrated in vacuo. The resulting yellow oil was dissolved in in dioxane (25 mL), treated with isoamyl nitrite (0.109 mL, 0.815 mmol), stirred at 100° C. for 6 h, cooled to room temperature, filtered through Celite, concentrated in vacuo and triturated with Et₂O to give the title compound (110 mg, 46%) as a yellow solid.

Method O

(5-Amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)acetic acid Example 26

A solution of ethyl 5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylacetate (547 mg, 1.89 mmol) in MeOH (5 mL) was treated with aqueous NaOH (2 mL, 2-M, 4 mmol), refluxed for 10 min, cooled, acidified with aqueous HCl (1-M), filtered and dried to give the title compound (417 mg, 85%) as a white solid.

Method P

(5-Amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-N-(3-chlorophenyl)acetamide Example 31

A suspension of (5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)acetic acid (140 mg, 0.5 mmol) in DMF (1 mL) was treated with carbonyl diimidazole (81 mg, 0.5 mmol), stirred at room temperature for 1 h, treated with 3-chloroaniline (53 μL, 0.5 mmol) and the mixture heated to 50° C. for 16 h. The reaction mixture was cooled, diluted with water (3 mL) and filtered to give the title compound (94 mg, 48%) as a cream solid.

Method Q

3-(2-Fluorobenzyl)-7-(2-thiazolyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine Example 34

A stirred solution of thiazole (0.10 mL, 1.43 mmol) in dry THF (5 mL) at −78° C., under argon was treated with n-BuLi (0.9 mL, 1.6-M in hexanes, 1.43 mmol), stirred for 30 min, treated with a solution of ZnCl₂ (1.8 mL, 1-M in Et₂O, 1.80 mmol) and allowed to warm gradually to room temperature. The mixture was treated with 7-chloro-3-(2-fluorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (200 mg, 0.714 mmol) and Pd(PPh₃)₄ (50 mg), refluxed for 2 h and partitioned between saturated NH₄Cl (20 mL) and EtOAc (20 mL). The organic phase was dried (MgSO₄), concentrated in vacuo and purified by chromatography [SiO₂; iso-hexane:EtOAc (1:1)) to give the title compound (70 mg, 30%) as a cream solid.

Method R

N-(2-Amino-6-(2-furyl)-5-nitropyrimidine-4-yl)-6-chloropyridine-3-carboxamide

A solution of 6-(2-furyl)-5-nitropyrimidine-2,4-diamine (500 mg, 2.26 mmol) in pyridine (10 mL) was treated with 6-chloronicotinoyl chloride (438 mg, 2.49 mmol), stirred for 16 h at 80° C., cooled to room temperature, poured into water (100 mL) and extracted with EtOAc (2×25 mL) and the combined organic phase was dried (MgSO₄), concentrated in vacuo and purified by chromatography [SiO₂; isohexane:EtOAc (3:2)] to give the title compound (430 mg, 82%) as a yellow solid; NMR δ_(H) (400 MHz, DMSO) 11.14 (1H, s), 8.86 (1H, d, J 2.5 Hz), 8.27 (1H, dd, J 8.5, 2.5 Hz), 7.93 (1H, m), 7.77 (2H, br s), 7.65 (1H, d, J 7.5 Hz), 7.09 (1H, d, J 4.5 Hz), 6.72–6.70 (1H, m); Retention time 2.41 min.

Method T

6-Chloro-N-(7-(2-furyl)-1H-[2,3]triazolo[4,5-d]pyrimidin-5-yl)pyridine-3-carboxamide Example 44

A solution of N-(2-amino-6-(2-furyl)-5-nitropyrimidine-4-yl)-6-chloropyridine-3-carboxamide (153 mg, 0.423 mmol) and 10% Pd/C (82 mg, 42.3 μmol) in EtOH (20 mL) and EtOAc (5 mL) was stirred under an hydrogen atmosphere for 3 h, filtered through Celite and concentrated in vacuo to give N-(2,5-diamino-6-(2-furyl)pyrimidin-4-yl)-6-chloropyridine-3-carboxamide as a yellow oil. A solution of this product in EtOH (5 mL) and 2-M HCl (5 mL) at 0° C. was treated dropwise with an ice-cold solution of sodium nitrite (87 mg, 1.27 mmol) in water (2 mL). The mixture was stirred at 0° C. for 1 h, stirred at room temperature for 1 h, neutralised with 5-M NaOH, stirred for 16 h and the resulting solid was filtered to give title compound (40 mg, 28%) as a brown solid.

Method U

6-Chloro-N⁴-(3-nitrobenzyl)pyrimidine-2,4,5-triamine

A mixture of 4,6-dichloropyrimidine-2,5-diamine (700 mg, 3.91 mmol), 3-nitrobenzylamine hydrochloride (885 mg, 4.69 mmol) and triethylamine (1.6 mL, 11.7 mmol) in n-BuOH (20 mL) was refluxed for 17 h, concentrated in vacuo and the residue partitioned between EtOAc (10 mL) and H₂O (5 mL). The organic phase was dried (MgSO₄) and concentrated in vacuo to give the title compound as an orange solid (906 mg, 76%) which was used in the next reaction without further purification; NMR δ_(H) (400 MHz, CDCl₃) 8.16 (1H, s), 8.10 (1H, d, J 8.0 Hz), 7.80 (1H, d, J 7.5 Hz), 7.62 (1H, t, J 7.5 Hz), 7.25 (1H, t, J 6.0 Hz), 5.69 (2H, s), 4.67 (2H, d, J 6.0 Hz) and 3.93 (2H, br s).

Method V

3-Chloromethyl-N,N-dimethylbenzamide

A solution of 3-(chloromethyl)benzoyl chloride (426 μL, 3 mmol) and Et₃N (626 μL, 4.5 mmol) in THF (5 mL) was treated with dimethylamine (1.5 mL, 2-M in THF, 3 mmol), stirred at room temperature for 1 h, poured into water, extracted with EtOAc, dried (MgSO₄) and concentrated in vacuo to give the title compound (580 mg, 98%) as a colourless oil; NMR δ_(H) (400 MHz, CDCl₃) 7.46–7.34 (4H, m), 4.59 (2H, s), 3.11 (3H, s) and 2.98 (3H, s); Anal. Calcd for C₁₂H₁₂N₆O₂. 0.2H₂O: C, 49.38; H, 4.28, N, 28.79.Found: C, 49.25; H, 4.09; N, 28.47.

Method W

7-(2-Furyl)-3-(2-methoxy-5-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine Example 66

A solution of 7-(2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrmidine-5-amine (606 mg, 3 mmol) in DMF (5 mL) at 0° C., was treated with CsCO₃ (977 mg, 3 mmol), stirred for 1 h, treated with 2-methoxy-5-nitrobenzyl bromide (738 mg, 3 mmol) and stirred at room temperature for 1 h. The reaction mixture was diluted with water (10 mL), filtered and the resulting solid purified by chromatography [SiO₂; EtOAc:Heptane (2:1)] to give the title compound (279 mg, 25%) as a yellow solid.

Method X

3-(2-Fluorobenzyl)-7-(5-oxazolyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine Example 69

A stirred solution of oxazole (138 mg, 2.0 mmol) in dry THF (10 mL) at −78° C., under argon was treated with n-BuLi (1.25 mL, 1.6-M in hexanes, 2.0 mmol), stirred for 30 min, treated with a solution of ZnCl₂ (2.0 mL, 1-M in Et₂O, 2.0 mmol)) and allowed to warm gradually to room temperature. The mixture was treated with 7-chloro-3-(2-fluorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (280 mg, 1.0 mmol) and Pd(PPh₃)₄ (100 mg), refluxed for 4 h and partitioned between saturated NH₄Cl solution (10 mL) and EtOAc (10 mL). The organic phase was dried (MgSO₄), concentrated in vacuo and purified by chromatography [SiO₂; iso-hexane:EtOAc (1:1), then neat EtOAc] to give the title compound (6 mg, 2%) as a beige solid.

Method Y

3-(2-Fluorobenzyl)-7-(1H-triazol-4-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine Example 80

A mixture of 7-chloro-3-(2-fluorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (145 mg, 0.50 mmol), tributyl 1-(2-(trimethylsilyl)ethoxymethyl)-1H-triazol-5-ylstannane (336 mg, 0.75 mmol) and Pd(PPh₃)₂Cl₂ (35 mg, 0.05 mmol) in DMF (2 mL) was shaken at 80° C. for 17 h then purified directly by chromatography [SiO₂; iso-hexane:EtOAc (2:1)] to give 3-(2-fluorobenzyl)-7-(1-(2-trimethylsilyl)ethoxymethyl)-1H-triazol-5-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine as a colourless oil. This material was dissolved in MeOH (1 mL), treated with a solution of HCl (0.5 mL, 4-M in dioxane), stirred for 17 h, concentrated in vacuo and the residue triturated with Et₂O to give the title compound (16 mg, 10%) as an off-white solid.

Method Z

3-(4-Hydroxylamino-2pyridylmethyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine Example 87

A solution of 7-(5-methyl-2-furyl)-3-(4-nitro-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (60 mg, 0.17 mmol) in EtOH (40 mL), MeOH (20 mL) and water (15 mL) was treated with ammonium chloride (280 mg, 5.23 mmol) and zinc (138 mg, 2.05 mmol), stirred for 1 h, filtered through Celite, concentrated in vacuo to ˜20 mL, diluted with brine (20 mL), extracted with EtOAc (3×20 mL) and the combined organic phase dried (MgSO₄) and concentrated in vacuo to give the title compound (40 mg, 73%) as a yellow solid.

Method AA

3-(3-Aminomethylbenzyl)-7-(1H-pyrazol-3-yl)-3H-[1,2,3]triazolo[4,5d]pyrimidine-5-amine Example 101

A stirred solution of the 7-(1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrazol-5-yl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (330 mg, 1 mmol) in dry DMF (5 mL) was treated with NaH (40 mg, 60% in oil, 1 mmol), stirred for 15 min, treated with tert-butyl N-(3-(bromomethyl)benzyl)carbamate (300 mg, 1 mmol) and stirred for 1 h. The mixture was partitioned between EtOAc (20 mL) and H₂O (20 mL), the organic phase was dried (MgSO₄), concentrated in vacuo and purified by chromatography [SiO₂; iso-hexane:EtOAc (1:1)]. The resulting yellow syrup was dissolved in MeOH (3 mL), treated with HCl (2 mL, 4-M in dioxane), stirred for 17 h and the resulting solid filtered to give the title compound (258 mg, 80%) as a cream solid.

Method AB

2-Bromomethyl-6-(methoxymethyl)pyridine

A solution of 6-methoxymethyl-2-pyridinemethanol (860 mg, 5.64 mmol) and triphenylphosphine (1.78 g, 6.77 mmol) in dichloromethane (40 mL) at 0° C. was treated portion wise with CBr₄ (2.80 g, 8.43 mmol), stirred for 1 h, concentrated in vacuo and purified by chromatography [SiO₂; isohexane:EtOAc (3:1)] to give the title compound (1.20 g, 99%) as a colourless oil; NMR δ_(H) (400 MHz, CDCl₃) 7.71 (1H, t, J 8.0 Hz), 7.35 (2H, d, J 8.0 Hz), 4.58 (2H, s) and 4.54 (2H, s).

The following novel compounds were also synthesised by Method AB from the appropriate alcohol.

2-Bromomethyl-4-methylpyridine

NMR δ_(H) (400 MHz, CDCl₃) 8.43 (1H, d, J 5.0 Hz), 7.26–7.25 (1H, m), 7.03 (1H, d, J 5.0 Hz), 4.51 (2H, s) and 2.36 (3H, s).

2-Bromomethyl-6-ethylpyridine

NMR δ_(H) (400 MHz, CDCl₃) 7.60 (1H, t, J 7.5 Hz), 7.26 (1H, d, J 7.5 Hz), 7.08 (1H, d, J 7.5 Hz), 4.53 (2H, s), 2.82 (2H, q, J 7.5 Hz) and 1.30 (3H, t, J 7.5 Hz).

4-Bromomethyl-2-ethylpyridine

NMR δ_(H) (400 MHz, CDCl₃) 8.51 (1H, d, J 5.0 Hz), 7.17–7.16 (1H, m), 7.13–7.11 (1H, m), 4.37 (2H, s), 2.84 (2H, q, J 7.5 Hz) and 1.32 (3H, t, J 7.5 Hz).

tert-Butyl (4-bromomethyl-3,5-difluorophenyl) carbonate

NMR δ_(H) (400 MHz, CDCl₃) 6.80 (2H, m), 4.49 (2H, s) and 1.56 (9H, s).

2-Fluoro-5-iodobenzyl bromide

NMR δ_(H) (400 MHz, DMSO) 7.94–7.91 (1H, dd, J 2.5, 7.5 Hz), 7.76–7.71 (1H, m), 7.12–7.06 (1H, dd, J 8.5, 10.0 Hz) and 4.66–4.64 (2H, s).

2-Allyloxymethyl-6-bromomethylpyridine

NMR δ_(H) (400 MHz, CDCl₃) 7.71 (1H, t, J 7.5 Hz), 7.40 (1H, d, J 7.5 Hz), 7.34 (1H, d, J 7.5 Hz), 6.03–5.93 (1H, m), 5.37–5.32 (1H, m), 5.26–5.22 (1H, m), 4.64 (2H, s), 4.54 (2H, s) and 4.14–4.12 (2H1, m).

4-Nitro-2-(2-trimethylsilylethoxy)methoxybenzyl bromide

NMR δ_(H) (400 MHz, CDCl₃) 7.99 (1H, d, J 2.0 Hz), 7.84 (1H, dd, J 8.4, 2.0 Hz), 7.49 (1H, d, J 8.4 Hz), 5.41 (2H, s), 4.55 (2H, s), 3.82 (2H, m), 0.96 (2H, m) and 0.01 (9H, s).

2-Bromomethyl-4,6-diisopropylpyridine

NMR δ_(H) (400 MHz, CDCl₃) 7.12 (1H, s), 6.93 (1H, s), 4.52 (2H, s), 3.03 (1H, sept, J 7.0 Hz), 2.87 (1H, sept, J 7.0 Hz), 1.29 (6H, d, J 7.0 Hz) and 1.25 (6H, d, J 7.0 Hz).

2-Bromomethyl-6-isopropylpyridine

NMR δ_(H) (400 MHz, CDCl₃) 7.63–7.59 (1H, m), 7.27–7.25 (1H, m), 7.10–7.08 (1H, m), 4.54 (2H, s), 3.06 (1H, sept, J 7.0 Hz) and 1.30 (6H, d, J 7.0 Hz).

2-Bromomethyl-6-vinylpyridine

NMR δ_(H) (400 MHz, CDCl₃) 7.66 (1H, t, J 7.5 Hz), 7.34–7.28 (2H, m), 6.81 (1H, dd, J 10.5, 17.5 Hz), 6.22 (1H, dd, J 1.0, 17.5 Hz), 5.51 (1H, dd, J 1.0, 10.5 Hz) and 4.55 (2H, s).

2-Bromomethyl-5-ethylthiophene

NMR δ_(H) (400 MHz, DMSO) 6.85–6.82 (1H, d, J 3.5 Hz), 6.71–6.68 (1H, d, J 3.5 Hz), 4.59–4.55 (2H, s), 2.81–2.75 (2H, m) and 1.25–1.20 (3H, m).

2-Bromomethyl-6-n-propylpyridine

NMR δ_(H) (400 MHz, CDCl₃) 7.59 (1H, t, J 7.5 Hz), 7.26 (1H, d, J 7.5 Hz), 7.06 (1H, d, J 7.5 Hz), 4.53 (2H, s), 2.76 (2H, t, J 7.5 Hz), 1.74 (2H, t, sext, J 7.5 Hz) and 0.97 (3H, t, J 7.5 Hz).

2-Bromomethyl-6-isobutyloxymethylpyridine

NMR δ_(H) (400 MHz, CDCl₃) 7.71 (1H, t, J 7.5 Hz), 7.41 (1H, d, J 7.5 Hz), 7.33 (1H, d, J 7.5 Hz), 4.62 (2H, s), 4.53 (2H, s), 3.33 (2H, d, J 6.5 Hz), 1.91–2.01 (1H, m) and 0.96 (6H, d, J 6.5 Hz).

5-Bromomethyl-2-isopropylpyridine

NMR δ_(H) (400 MHz, CDCl₃) 8.54 (1H, m), 7.65 (1H, dd, J 2.5, 8.0 Hz), 7.16 (1H, d, J 8.0 Hz), 4.47 (2H, s), 3.07 (1H, sept, J 7.0 Hz) and 1.30 (6H, d, J 7.0 Hz).

2-Bromomethyl-6-isopropyloxymethylpyridine

NMR δ_(H) (400 MHz, CDCl₃) 7.71–7.67 (1H, m), 7.42–7.40 (1H, m), 7.33–7.31 (1H, m), 4.63 (2H, s), 4.53 (2H, s), 3.75 (1H, sept, J 6.0 Hz) and 1.25 (6H, d, J 6.0 Hz).

Method AC

2-Bromomethyl-4-nitropyridine

A solution of 2-methyl-4-nitropyridine (1.79 g, 13.0 mmol) in CCl₄ (30 mL) was treated with N-bromosuccinimide (2.31 g, 13.0 mmol) and benzoyl peroxide (420 mg, 1.30 mmol), stirred at 80° C. for 16 h, cooled to room temperature, filtered through Celite, concentrated in vacuo and purified by chromatography [SiO₂; isohexane:EtOAc (15:1)] to give the title compound (700 mg, 25%) as a colourless oil; NMR δ_(H) (400 MHz, CDCl₃) 8.89 (1H, d, J 5.0 Hz), 8.19 (1H, d, J 2.0 Hz), 7.96 (1H, dd, J 5.0, 2.0 Hz) and 4.66 (2H, s).

The following novel compounds were also synthesised by bromination of the appropriate arylalkyl compounds using Method AC.

2-Bromomethyl-6-methyl-4-nitropyridine

NMR δ_(H) (400 MHz, CDCl₃) 7.99–7.98 (1H, m), 7.79 (1H, d, J 2.0 Hz), 4.60 (2H, s) and 2.71 (3H, s).

tert-Butyl 7-bromomethylindole-1-carboxylate

NMR δ_(H) (400 MHz, CDCl₃) 7.57 (1H, d, J 4.0 Hz), 7.55 (1H, dd, J 8.0, 1.5 Hz), 7.27 (1H, d, J 7.5 Hz), 7.19 (1H, t, J 7.5 Hz), 6.58 (1H, d, J 3.5 Hz), 5.24 (2H, s) and 1.68 (9H, s).

tert-Butyl 5-bromomethylindole-1-carboxylate

NMR δ_(H) (400 MHz, CDCl₃) 8.11 (1H, br d, J 8.5 Hz), 6.72 (1H, d, J 3.5 Hz), 7.59 (1H, d, J 1.5 Hz), 7.35 (1H, dd, J 8.5, 1.5 Hz), 6.54 (1H, d, J 4.0 Hz), 4.64 (2H, s) and 1.67 (9H, s).

tert-Butyl 7-bromomethyl-5-chloroindole-1-carboxylate

NMR δ_(H) (400 MHz, CDCl₃) 7.58 (1H, d, J 3.5 Hz), 7.51 (1H, d, J 2.0 Hz), 7.27 (1H, m), 6.52 (1H, d, J3.5 Hz), 5.15 (2H, s), and 1.67 (9H, s).

tert-Butyl 7-bromomethyl-5-methylindole-1-carboxylate

NMR δ_(H) (400 MHz, CDCl₃) 7.53 (1H, d, J 4.0 Hz), 7.32 (1H, s), 7.09 (1H, s), 6.49 (1H, d, J 3.5 Hz), 5.21 (2H, s), 2.41 (3H, s) and 1.66 (9H, s).

tert-Butyl 5-bromomethyl-7-fluoroindole-1-carboxylate

NMR δ_(H) (CDCl₃) 7.65 (1H, d, J 4.0 Hz), 7.35 (1H, d, J 1.5 Hz), 7.07 (1H, dd, J 13.0, 1.5 Hz), 6.56 (1H, dd, J 3.5, 1.5 Hz), 4.56 (2H, s) and 1.65 (9H, s).

tert-Butyl 5-bromomethyl-4-chloroindole-1-carboxylate

NMR δ_(H) (400 MHz, CDCl₃) 8.03 (1H, d, J 8.5 Hz), 7.63 (1H, d, J 4.0 Hz), 7.36 (1H, d, 8.5 Hz), 6.71 (1H, d, J 3.5 Hz), 4.75 (2H, s) and 1.67 (9H, s).

tert-Butyl 7-bromo-5-bromomethylindole-1-carboxylate

NMR δ_(H) (400 MHz, CDCl₃) 7.57 (1H, s), 7.56–7.52 (2H, m), 6.54 (1H, d, J 3.5 Hz), 4.56 (2H, s) and 1.66 (9H, s).

tert-Butyl 5-bromomethyl-6-chloroindole-1-carboxylate

NMR δ_(H) (400 MHz, CDCl₃) 8.23 (1H, br s), 7.60 (1H, s), 7.58 (1H, d, J 3.5 Hz), 6.51 (1H, d, J 4.5 Hz), 4.71 (2H, s) and 1.67 (9H, s).

tert-Butyl 5-bromomethyl-6-fluoroindole-1-carboxylate

NMR δ_(H) (400 MHz, CDCl₃) 7.88 (1H, br, d, J 11.0 Hz), 7.57 (1H, d, J 4.0 Hz), 7.54 (1H, d, J 7.0 Hz), 6.52 (1H, d, J 4.5 Hz), 4.64 (2H, s) and 1.67 (9H, s).

tert-Butyl 2-bromomethyl-5-fluoroindole-1-carboxylate

NMR δ_(H) (400 MHz, CDCl₃) 8.12 (1H, dd, J 9.0, 4.5 Hz), 7.15 (1H, dd, J 8.5, 2.5 Hz), 7.04 (1H, dt, J 9.0, 2.5 Hz), 6.66 (1H, s), 4.90 (2H, s) and 1.72 (9H, s).

tert-Butyl 5-bromomethyl-7-chloroindole-1-carboxylate

NMR δ_(H) (400 MHz, CDCl₃) 7.56 (1H, d, J 4.0 Hz), 7.49 (1H, d, J 2.0 Hz), 7.37 (1H, s), 6.54 (1H, d, J 3.5 Hz), 4.56 (2H, s) and 1.65 (9H, s).

2-(1-Bromopropyl)-5,6-dimethylpyridine

NMR δ_(H) (400 MHz, CDCl₃) 7.39 (1H, d, J 8.0 Hz), 7.18 (1H, d, J 8.0 Hz), 4.93 (1H, t, J 7.5 Hz), 2.49 (3H, s), 2.27 (3H, s), 2.29–2.24 (2H, m) and 1.02 (3H, t, J 7.0 Hz); M/Z 228 (M+H)⁺.

The following novel compound was synthesised by bromination of 2-(1-methoxypropyl)-6-methylpyridine using Method AC.

2-Bromo-1-(6-methylpyridin-2-yl)propanone

NMR δ_(H) (400 MHz, CDCl₃) 7.91 (1H, d, J 7.5 Hz), 7.74 (1H, t, J 7.5 Hz), 7.35 (1H, d, J 7.5 Hz), 6.13 (1H, q, J 7.0 Hz), 2.62 (3H, s) and 1.89 (3H, d, J 7.0 Hz).

Method AD

tert-Butyl 7-methylindole-1-carboxylate

A stirred solution of 7-methylindole (1.18 g, 9 mmol) in dry ThF (50 mL) was treated with NaH (360 mg, 60% in oil, 9 mmol), stirred for 10 min, treated with di-tert-butyl dicarbonate (2.3 mL, 9.3 mmol), stirred for 1 h, treated with 4-(N,N-dimethylamino)pyridine (catalytic amount) and stirred for 1 h. The mixture was partitioned between EtOAc (50 mL) and saturated NH₄Cl solution (30 mL) and the organic phase was dried (MgSO₄), concentrated in vacuo, and purified by chromatography [SiO₂; iso-hexane:EtOAc (5:1)] to give the title compound (2.35 g, 100%) as an orange oil; NMR δ_(H) (400 MHz, CDCl₃) 7.51 (1H, d, J 4.0 Hz), 7.37 (1H, d, J 7.5 Hz), 7.13 (1H, t, J 7.5 Hz), 7.08 (1H, d, 7.5 Hz), 6.51 (1H, d, J 4.0 Hz), 2.64 (3H, s) and 1.63 (9H, s).

The following novel compounds were synthesised from the appropriate indoles using Method AD.

tert-Butyl 5-chloro-7-methylindole-1-carboxylate

NMR δ_(H) (400 MHz, CDCl₃) 7.52 (1H, d, J 4.0 Hz), 7.35 (1H, d, J 2.0 Hz), 7.07 (1H, d, J 1.5 Hz), 6.46 (1H, d, J 3.5 Hz), 2.61 (3H, s), and 1.63 (9H, s).

tert-Butyl 5,7-dimethylindole-1-carboxylate

NMR δ_(H) (CDCl₃) 7.48 (1H, d, J 4.0 Hz) 7.16 (1H, s), 6.92 (1H, s), 6.44 (1H, d, J 4.0 Hz), 2.60 (3H, s) 2.38 (3H, s) and 1.62 (9H, s).

tert-Butyl 7-fluoro-5-methylindole-1-carboxylate

NMR δ_(H) (CDCl₃) 7.59 (1H, d, J4.0 Hz), 7.10 (1H, s), 6.84 (1H, d, J 13.5 Hz), 6.50–6.47 (1H, m), 2.40 (3H, s) and 1.64 (9H, s).

tert-Butyl 4-chloro-5-methylindole-1-carboxylate

NMR δ_(H) (400 MHz, CDCl₃) 7.92 (1H, d, J 8.0 Hz), 7.57 (1H, d, J 3.5 Hz), 7.15 (1H, d, J 8.5 Hz), 6.66 (1H, d, J 3.5 Hz), 2.46 (3H, s) and 1.66 (9H, s).

tert-Butyl 7-bromo-5-methylindole-1-carboxylate

NMR δ_(H) (400 MHz, CDCl₃) 7.47 (1H, d, J 3.5 Hz), 7.35 (1H, s), 7.26 (1H, s), 6.44 (1H, d, J 4.0 Hz), 2.38 (3H, s) and 1.64 (9H, s).

tert-Butyl 6-chloro-5-methylindole-1-carboxylate

NMR δ_(H) (400 MHz, CDCl₃) 8.17 (1H, br s), 7.53 (1H, d, J 3.5 Hz), 7.38 (1H, s), 6.46 (1H, d, J 3.0 Hz), 2.44 (3H, s), 1.67 (9H, s).

tert-Butyl 6-fluoro-5-methylindole-1-carboxylate

NMR δ_(H) (400 MHz, CDCl₃) 7.79 (1H, br d, J 10.5 Hz), 7.51 (1H, d, J 3.5 Hz), 7.30 (1H, d, J 7.5 Hz), 6.46 (1H, d, J 3.5 Hz), 2.34 (3H, s) and 1.66 (9H, s).

tert-Butyl 5-fluoro-2-methylindole-1-carboxylate

NMR δ_(H) (400 MHz, CDCl₃) 8.04 (1H, dd, J 9.0, 4.5 Hz), 7.07 (1H, dd J 9.0, 2.5 Hz), 6.92 (1H, dt, J 9.5, 3.0 Hz), 6.27 (1H, s), 2.58 (3H, d, J 1.5 Hz) and 1.67 (9H, s).

tert-Butyl 7-chloro-5-methylindole-1-carboxylate

NMR δ_(H) (400 MHz, CDCl₃) 7.50 (1H, d, J 3.5 Hz), 7.22 (1H, s), 7.14 (1H, s), 6.46 (1H, d, J 4.0 Hz), 2.38 (3H, s) and 1.64 (9H, s).

The following novel compound was synthesised from 2,6-difluoro-4-hydroxybenzyl alcohol using Method AD.

tert-Butyl (3,5-difluoro-4-hydroxymethylphenyl) carbonate

IR ν_(max) (DR)/cm⁻¹ 3388, 2983, 1775, 1605, 1446, 1396, 1373, 1289, 1146, 1072, 967 and 882; NMR δ_(H) (400 MHz, CDCl₃) 6.79 (2H, m), 4.75 (2H, d, J 6.5 Hz), 1.84 (1H, t, J 6.5 Hz) and 1.56 (9H, s).

Method AE

2,6-Difluoro-4-hydroxybenzyl alcohol

A mixture of 3,5-difluorophenol (25 g, 0.19 mol) and KOH (85%, 12.7 g, 0.19 mol) was treated dropwise with water (50 mL), stirred at 60° C. for 1 h, treated dropwise with formaldehyde solution (37%, 15.6 mL, 0.19 mol) and water (50 mL) and stirred overnight at 40° C. The mixture was cooled, acidified with 6-M HCl, filtered and the resulting solid washed with water and dried to give the title compound (15 g, 49%) as a white solid: NMR δ_(H) (400 MHz, DMSO) 10.28 (1H, s), 6.43 (2H, m), 4.99 (1H, t, J 5.6 Hz) and 4.37 (2H, d, J 5.6 Hz).

Method AF

7-(2-Furyl)-3-(6-indolylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine Example 152

A mixture of tert-butyl 6-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-ylmethyl)indole-1-carboxylate (135 mg, 4.08 mmol), and NaOMe (22 mg, 4.08 mmol) in MeOH (10 mL) was refluxed for 1 h, treated with NaOMe (110 mg, 20.4 mmol), refluxed for a further 4 h then stirred at room temperature for 17 h. The mixture was concentrated in vacuo to half volume and the resulting precipitate was filtered and washed with H₂O to give the title compound (90 mg, 96%) as a cream solid.

Method AG

3-(2,6-Difluoro-4-methoxybenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine Example 156

A solution of 3-(2,6-difluoro-4-hydroxybenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine hydrochloride (130 mg, 0.34 mmol) in DMF (5 mL) at 0° C., was treated with CsCO₃ (223 mg, 0.68 mmol), stirred for 10 min, treated with methyl iodide (21 μL, 0.34 mmol) and stirred at room temperature for 30 min. The reaction mixture was diluted with water (10 mL) and filtered to give the title compound (122 mg, 100%) as a white solid.

Method AH

2-Fluoro-5-iodobenzyl alcohol

A solution of 2-fluoro-5-iodobenzaldehyde (1.173 g, 4.692 mmol) in isopropanol (25 mL) was treated with sodium borohydride (0.379 g, 10.02 mmol), stirred at room temperature for 18 h, poured into water (125 mL), and extracted with isopropyl ether (2×25 mL). The combined organic phase was dried (Na₂SO₄), and concentrated in vacuo to give the title compound (1.187 g, 99%) as a pale yellow solid; NMR δ_(H) (400 MHz, CDCl₃) 7.77 (1H, m), 7.57 (1H, m), 6.82 (1H, t, J 8.8 Hz), 4.73 (2H, d, J 6.1 Hz), and 1.79 (1H, t, J 6.1 Hz).

Method AI

3-(tert-Butoxycarbonyloxy)-4-nitrobenzoic acid

A solution of 3-hydroxy-4-nitrobenzoic acid (1.83 g, 10 mmol) in THF (10 mL) was treated with Et₃N (3.4 mL, 24 mmol) and di-tert-butyl dicarbonate (2.40 mL, 11 mmol) and stirred at room temperature for 16 h. The reaction mixture was poured into 10% citric acid solution (20 mL), extracted with EtOAc (2×10 mL), dried (MgSO₄) and concentrated in vacuo to give the title compound (2.36 g, 83%) as a cream solid; IR ν_(max) (Nujol)/cm⁻¹ 2985, 1772, 1717 and 1592; NMR δ_(H) (400 MHz, DMSO) 13.85 (1H, s), 8.26 (1H, d, 8.5 Hz), 8.04 (1H, dd, J 8.5, 2.0 Hz), 7.98 (1H, d, J 2.0 Hz) and 1.49 (9H, s).

Method AJ

tert-Butyl (5-bromomethyl-2-nitrophenyl) carbonate

A solution of 3-(tert-butoxycarbonyloxy)-4-nitrobenzoic acid (2.26 g, 8 mmol) and N-methylmorpholine (1.85 mL, 16.8 mmol) in THF (20 mL) at 0° C., was treated with isobutylchloroformate (1.09 mL, 8.4 mmol) and stirred for 1 h. The reaction mixture was added to a cooled (−78° C.) solution of NaBH₄ (605 mg, 16 mmol) in MeOH (16 mL) and stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc (20 mL), washed with saturated NaHCO₃ (10 mL) and 10% citric acid solution (10 mL), dried (MgSO₄) and concentrated in vacuo to give tert-butyl (5-hydroxymethyl-2-nitrophenyl) carbonate (1.36 g, 86%) as a cream solid. This material was brominated directly using Method AB to give the title compound (961 mg, 58%) as a yellow oil: NMR δ_(H) (400 MHz, CDCl₃) 8.09 (1H, d, J 8.4 Hz), 7.41 (1H, dd, J 8.4, 2.0 Hz), 7.34 (1H, d, J 2.0 Hz), 4.47 (2H, s) and 1.58 (9H, s).

Method AK

3-(3-Nitrobenzyl)-7-(1H-pyrazol-3-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine hydrochloride Example 266

A soluition of 7-chloro-3-(3-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (306 mg, 1 mmol), 1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrazol-5-ylboronic acid (2 mmol), Pd(PPh₃)₄ (100 mg) and saturated NaHCO₃ (5 mL) in THF (20 mL) was refluxed for 2 h, diluted with water (20 mL), extracted with EtOAc(2×20 mL), dried (MgSO₄), concentrated in vacuo and purified by chromatography [SiO₂; CH₂Cl₂:EtOAc (6:1)] to give 3-(3-nitrobenzyl)-7-(1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrazol-5-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (156 mg, 34%) as a pale yellow syrup.

A solution of 3-(3-nitrobenzyl)-7-(1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrazol-5-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (156 mg, 0.34 mmol) in MeOH (2 mL) was treated with 4-M HCl in dioxane (4 mL) stirred at room temperature for 2 h, concentrated in vacuo, triturated with Et₂O and filtered to give the title compound (110 mg, 97%) as a yellow solid.

Method AL

3-(6-Acetamidomethyl-2-pyridylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine Example 177

A suspension of 7-(2-furyl)-3-(6-phthalimidomethyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (210 mg, 0.465 mmol) in EtOH (50 mL) was treated with ethylenediamine (62 μl, 0.929 mmol), stirred for 3 h at 90° C. and the resulting clear solution, cooled to room temperature and concentrated in vacuo to give 3-(6-aminomethyl-2-pyridylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine. A solution of this material in pyridine (10 mL) at 0° C. was treated with acetyl chloride (109 ml, 1.53 mmol), stirred for 10 min, poured into water (70 mL), extracted with EtOAc (3×20 mL) and the combined organic phase was dried (MgSO₄), concentrated in vacuo and purified by chromatography [SiO₂; EtOAc] to give the title compound (110 mg, 65%) as a beige solid.

Method AM

3-(6-Allyloxymethyl-2-pyridylmethyl)-N,N-dialkyl-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine Example 182

A solution of 7-(2-furyl)-3-(6-hydroxymethyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (120 mg, 0.377 mmol) in DMF (5 mL) at 0° C. was treated with sodium hydride (30 mg, 0.743 mmol), stirred for 15 min, treated with alkyl bromide (96 μl, 1.11 mmol), stirred at room temperature for 16 h, concentrated in vacuo to ˜2 mL and purified by chromatography [SiO₂; isohexane:EtOAc (3:1)] to give the title compound (50 mg, 30%) as a yellow solid.

Method AN

6-Allyloxymethyl-2-pyridinemethanol

A solution of 2,6-pyridinedimethanol (5.0 g, 35.9 mmol) in DMF (30 mL) at 0° C. was treated with sodium hydride (1.44 g, 35.9 mmol), stirred for 30 min, treated with alkyl bromide (3.42 ml, 39.5 mmol), stirred for 16 h at room temperature, poured into water (150 mL), extracted with EtOAc (3×30 mL) and the combined organic phase was dried (MgSO₄), concentrated in vacuo and purified by chromatography [SiO₂; isohexane:EtOAc (3:1 to 1:1)] to give the title compound (1.56 g, 24%) as a colourless oil: NMR δ_(H) (400 MHz, CDCl₃) 7.69 (1H, t, J 7.5 Hz), 7.37 (1H, d, J 7.5 Hz), 7.13 (1H, d, J 7.5 Hz), 6.04–5.93 (1H, m), 5.38–5.21 (2H, m), 4.74 (2H, d, J 5.0 Hz), 4.65 (2H, s), 4.15–4.09 (2H, m) and 3.76 (1H, t, J 5.0 Hz).

The following novel compounds were synthesised from the appropriate alcohols by Method AN

2-(1-Methoxypropyl)-6-methylpyridine

NMR δ_(H) (400 MHz, CDCl₃) 7.58 (1H, t, J 8.0 Hz), 7.18 (1H, d, J 8.0 Hz), 7.04 (1H, d, J 8.0 Hz), 4.17 (1H, dd, J 5.5, 7.5 Hz), 3.30 (3H, s), 2.55 (3H, s), 1.84–1.69 (2H, m) and 0.93 (3H, t, J 7.5 Hz).

6-Isobutyloxymethylpyridine-2-methanol

NMR δ_(H) (400 MHz, CDCl₃) 7.69 (1H, t, J 7.5 Hz), 7.37 (1H, d, J 7.5 Hz), 7.13 (1H, d, J 7.5 Hz), 4.74 (2H, s), 4.63 (2H, s), 3.94 (1H, br s), 3.33 (2H, d, J 6.5 Hz), 1.91–2.01 (1H, m) and 0.96 (6H, d, J 6.5 Hz).

6-Isopropyloxymethylpyridine-2-methanol

NMR δ_(H) (400 MHz, CDCl₃) 7.70–7.66 (1H, m), 7.39 (1H, d, J 7.5 Hz), 7.11 (1H, d, J 8.0 Hz), 4.74 (2H, s), 4.64 (2H, s), 3.75 (1H, sept, J 6.0 Hz) and 1.25 (6H, d, J 6.0 Hz).

Method AO

3-Isopropyl-4-nitrobenzyl bromide

A solution of 4-nitrobenzyl bromide (432 mg, 2 mmol) in THF (5 mL) at −70° C., was treated dropwise with isopropylmagnesium chloride (1 mL, 2-M in Et₂O, 2 mmol), stirred for 1 h, treated with DDQ (499 mg, 2.2 mmol) and stirred at room temperature for 16 h. The reaction mixture was poured into water (10 mL), extracted with EtOAc (2×10 mL), dried (MgSO₄), concentrated in vacuo and filtered. The resulting solid was purified by chromatography [SiO₂; EtOAc:Heptane (1:4)] to give the title compound (183 mg, 35%) as a pale yellow solid which was used in the next reaction without further purification.

The following novel compound was also synthesised from 4-nitrobenzyl bromide using Method AO

3-Ethyl-4-nitrobenzyl bromide

NMR δ_(H) (400 MHz, CDCl₃) 7.87 (1H, d, J 8.3 Hz), 7.37 (1H, s), 7.35 (1H, d, J 8.3 Hz), 4.47 (2H, s), 2.92 (2H, q, J 7.5 Hz) and 1.30 (3H, t, J 7.5 Hz).

Method AP

2-(Trimethylsilyl)ethoxymethyl 4-nitro-2-((2-trimethylsilyl)ethoxymethoxy)benzoic acid

A solution of 2-hydroxy-4-nitrobenzoic acid (1.83 g, 10 mmol) in THF (20 mL), was treated with N,N-diisopropylethylamine (3.92 mL, 22 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (3.46 mL, 20 mmol) and stirred for 16 h then purified directly by chromatography [SiO₂:EtOAc:heptane (1:4)] to give the title compound (5.82 mg, quantitative) as white solid which was used in the next reaction without further purification; NMR δ_(H) (400 MHz, CDCl₃) 8.09–8.07 (1H, m), 7.87–7.85 (2H, m), 5.50 (2H, s), 5.35 (2H, s), 3.78 (4H, t, J 8.5 Hz), 1.00–0.88 (4H, m), 0.00 (9H, s) and 0.03 (9H, s).

Method AQ

2-(2-Trimethylsilyl)ethoxymethoxy-4-nitrobenzyl alcohol

A solution of 2-(trimethylsilyl)ethoxymethyl 4-nitro-2-(2-(trimethylsilyl)ethoxymethoxy)benzoic acid (2.91 mg, 5 mmol) in Et₂O (10 mL) at 0° C., was treated with LiAlH₄ (190 mg, 22 mmol) and stirred for 30 min. The reaction mixture was poured into water (20 mL), extracted with EtOAc (2×10 mL), dried (MgSO₄) and concentrated in vacuo to give the title compound (1.35 g, 91%) as a slightly impure colourless oil; NMR δ_(H) (400 MHz, CDCl₃) 7.96–7.99 (1H, m), 7.90 (1H, dd, J 8.5, 2.0 Hz), 7.55 (1H, d, J 8.5 Hz), 5.35 (2H, s), 4.78 (2H, s), 3.80–3.74 (2H, m), 0.99–0.94 (2H, m) and 0.00 (9H, s).

Method AR

4,6-Diisopropyl-2-pyridinemethanol

A solution of 2-pyridinemethanol (5.00 g, 45.8 mmol), conc. sulfuric acid (2.44 ml, 45.8 mmol), iron(II) sulfate heptahydrate (1.53 g, 5.50 mmol) and isopropyl iodide (13.7 ml, 137 mmol) in DMSO (150 mL) was treated dropwise with hydrogen peroxide (27.5 wt % in H₂O, 17.0 mL, 137 mmol), with ice-bath cooling to maintain the internal temperature at 25–30° C. A further portion of iron(II) sulfate heptahydrate (1.53 g, 5.50 mmol) was added, the mixture was allowed to cool to room temperature over 1 h, poured into water (500 mL), basified to pH 9 with 5-M NaOH, extracted with dichloromethane (3×100 mL) and the combined organic phase was dried (MgSO₄), concentrated in vacuo and purified by chromatography [SiO₂; isohexane:EtOAc (3:2)] to give 4,6-diisopropyl-2-pyridinemethanol (500 mg, 6%) as a colourless oil; NMR δ_(H) (400 MHz, CDCl₃) 6.90 (1H, s), 6.85 (1H, s), 4.69 (2H, br s), 4.35 (1H, br s), 3.03 (1H, sept, J 7.0 Hz), 2.87 (1H, sept, J 7.0 MHz), 1.30 (6H, d, J 7.0 Hz) and 1.25 (6H, d, J 7.0 Hz), and 6-isopropyl-2-pyridinemethanol (900 mg, 13%) as a colourless oil.

The following novel compound was also synthesised from 2-pyridinemethanol by Method AR.

6-n-Propyl-2-pyridinemethanol

NMR δ_(H) (400 MHz, CDCl₃) 7.58 (1H, t, J 7.5 Hz), 7.03 (2H, t, J 7.5 Hz), 4.72 (2H, s), 4.15 (1H, br s), 2.77 (2H, t, J 7.5 Hz), 1.77 (2H, sept, J 7.5 Hz) and 0.97 (3H, t, J 7.5 Hz).

Method AS

tert-Butyl 5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-carboxylate Example 203

A solution of 7-(2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (300 mg, 1.49 mmol) in DMF (5 mL), at 0° C., was treated with 60% sodium hydride in mineral oil (60 mg, 1.49 mmol), stirred for 30 minutes, treated with tert-butyl 4-(bromomethyl)phenylcarbonate (471 mg, 1.64 mmol), stirred at room temperature for 16 h, and purified by chromatography [SiO₂; EtOAc:heptane, (1:2)] to give the title compound (55 mg, 12%) as a beige solid.

Method AT

2-(5-Amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-1-phenylethanone Example 211

A solution of 7-(2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (101 mg, 0.5 mmol) in DMF (2 mL) was treated with 2-bromoacetophenone (100 mg, 0.5 mmol) and triethylamine (105 μL, 0.75 mmol), stirred at room temperature for 3 days, diluted with water (100 mL) and filtered. The resulting solid was purified by chromatography [SiO₂; Hexane:EtOAc, (3:1 to 1:1)] to give the title compound (20 mg, 13%) as a yellow solid.

Method AU

7-(2-furyl)-3-(6-hydroxymethyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine hydrochloride Example 213

A solution of 6-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)pyridine-2-carboxaldehyde (62 mg, 0.193 mmol) in MeOH (20 mL) was treated with acetic acid (5 mL), dimethylamine (2-M in MeOH, 1.93 mL, 3.86 mmol) and sodium cyanoborohydride (242 mg, 3.86 mmol), stirred for 16 h and concentrated in vacuo. The residue was treated with saturated NaHCO₃ solution (20 mL), extracted with EtOAc (3×10 mL) and the combined organic phase dried (MgSO₄), concentrated in vacuo and purified by chromatography [SiO₂; EtOAc] to give the free base as a yellow solid. The solid was suspended in MeOH (1 mL), treated with HCl (4-M in dioxane, 0.25 mL), stirred for 10 min, concentrated in vacuo and triturated with Et₂O to give the title compound (22 mg, 29%) as a yellow solid.

Method AV

3-(6-Cyanomethyl-2-pyridylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine Example 220

A solution of 3-(6-bromomethyl-2-pyridylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (200 mg, 0.517 mmol) and sodium cyanide (51 mg, 1.03 mmol) in DMF (5 mL) was stirred at 60° C. for 16 h, poured into water (40 mL), extracted with EtOAc (3×8 mL), the combined organic phase dried (MgSO₄), concentrated in vacuo and purified by chromatography [SiO₂; isohexane:EtOAc (1:1)] to give title compound (50 mg, 26%) as a yellow solid.

Method AW

3-(4-Hydroxybenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine Example 221

A solution of 7-(2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5 amine (400 mg, 1.98 mmol) in DMF (3 mL), at 0° C., was treated with 60% sodium hydride in mineral oil (80 mg, 1.98 mmol), stirred for 30 min, treated with 4-(2-(trimethylsilyl)ethoxymethoxy)benzyl bromide (1.23 g, 3.96 mmol), stirred at room temperature for 48 h and purified by chromatography [SiO₂; EtOAc:heptane, (1:2)]. The resulting yellow solid was dissolved in MeOH:DMF (1:2), passed through an ion exchange cartridge (Isolute SPE SCX-2), concentrated in vacuo, and washed with water and ether to give the title compound (41 mg, 7%) as a pale yellow solid.

Method AX

N-(3-(5-Amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)phenyl)propanesulphonamide Example 224

A solution of 7-(2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (153 mg, 0.5 mmol) in pyridine (2 mL) at 0° C. was treated with propanesulfonyl chloride (62 μL, 0.55 mmol) and shaken at room temperature for 16 h. The mixture was poured into water (50 mL), extracted with EtOAc (2×10 mL), washed with 10% citric acid (10 mL) and the combined organic phase dried (MgSO₄) and concentrated in vacuo to give the title compound (111 mg, 54%) as a cream solid.

Method AY

7-(2-Furyl)-3-(6-(N-methylamino)methyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine Example 226

A solution of N-methyl-2,2,2-trifluoroacetamide (197 mg, 1.55 mmol) in DMF (5 mL) at 0° C. was treated with sodium hydride (60% dispersion in mineral oil; 62 mg, 1.55 mmol), stirred for 15 min, treated with 3-(6-bromomethyl-2-pyridylmethyl)-7-(2-furyl)-3-H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (120 mg, 0.310 mmol), stirred at 50° C. for 1 h, cooled to room temperature, poured into water (20 mL), extracted with EtOAc (3×10 mL) and the combined organic phase dried (MgSO₄) and concentrated in vacuo to give N-(6-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyimidin-3-ylmethyl)-2-pyridylmethyl)-N-methyltrifluoroacetamide. A solution of this product in MeOH (20 mL) was treated with a solution of sodium (71 mg, 3.10 mmol) in MeOH (10 rL), stirred for 16 h, concentrated in vacuo, treated with EtOAc (20 mL), filtered through Celite and concentrated in vacuo. The resulting solid was suspended in MeOH (2 mL), treated with HCl (4-M in dioxane, 1.0 mL), stirred for 10 min, concentrated in vacuo and triturated with Et₂O to give the title compound (80 mg, 58%) as a yellow solid.

Method AZ

3-(1H-Benzotriazol-5-ylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine Example 158

A mixture of 5-methyl-1H-benzotriazole (666 mg, 5 mmol) in THF (20 mL) was treated with NaH (60% dispersion, 200 mg, 5 mmol), stirred at room temperature for 10 min, treated with di-tert-butyl dicarbonate (115 mg, 5 mmol) and stirred overnight. The mixture was treated with saturated NaHCO₃ solution (10 mL), extracted with EtOAc (2×10 mL), dried MgSO₄), filtered through a plug of SiO₂ and concentrated in vacuo to give tert-butyl 5-methylbenzotriazole-1-carboxylate (as a mixture with the 6-methyl regioisomer) (1.08 g, 92%) as a colourless oil.

A solution of tert-butyl 5-methyl-1H-benzotriazole-1-carboxylate (as a mixture with the 6-methyl regioisomer) (1.08 g, 4.63 mmol), benzoyl peroxide (112 mg, 0.46 mmol) and N-bromosuccinnimide (0.76 g, 4.63 mmol) in CCl₄ (25 mL) was refluxed overnight, cooled, filtered, concentrated in vacuo and purified by chromatography [SiO₂; isohexane:EtOAc (10:1)] to give tert-butyl 5-(bromomethyl)-1H-benzotriazole-1-carboxylate (666 mg, 46%) (as a mixture with the 6-bromomethyl regioisomer) as a colourless oil.

A solution of 7-(2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (404 mg, 2 mmol) in DMF (4 mL) was treated with NaH (60% dispersion, 80 mg, 2 mmol), stirred at room temperature for 10 min, treated with a solution of tert-butyl 5-(bromomethyl)-1H-benzotriazole-1-carboxylate (as a mixture with the 6-bromomethyl regioisomer) (624 mg, 2 mmol) in DMF (2 mL) and stirred overnight. The mixture was concentrated in vacuo and purified by chromatography [SiO₂, isohexane:EtOAc (2:1)] to give tert-butyl 5-(5-amino-7-(2-furyl)-3H-triazolo[4,5-d]pyrimidin-3-yl)methyl-1H-benzotriazol-1-carboxylate (135 mg, 24%) (as a mixture with the 6-substituted regioisomer) as a white solid.

A solution of tert-butyl 5-(5-amino-7-(2-furyl)-3H-triazolo[4,5-d]pyrimidin-3-yl)methyl-1H-benzotriazol-1-carboxylate (as a mixture with the 6-substituted regioisomer) (135 mg, 0.31 mmol) in MeOH (5 mL) and THF (5 mL) was treated with 40% aqueous dimethylamine (0.176 mL, 1.56 mmol), refluxed for 25 min, concentrated in vacuo and the resulting solid triturated with ether, filtered, triturated with MeOH, filtered and dried to give the title compound (31 mg, 30%) as a yellow solid.

Method BA

Ethyl 4-((5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-yl)methyl)-2-methylphenylcarbamate Example 274

A suspension of 3-(4-amino-3-methylbenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (260 mg, 0.812 mmol) in pyridine (5 mL) at room temperature was treated dropwise with ethyl chloroformate (0.155 mL, 1.62 mmol), stirred for 30 min, poured into water (30 mL), extracted with EtOAc (2×10 mL) and the combined organic phase was dried (MgSO₄) and concentrated in vacuo to give the title compound (318 mg, 100%) as a beige solid.

Method BB

N-(4-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)-2-methylphenyl)formamide Example 244

A mixture of ethyl 4-((5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-yl)methyl)-2-methylphenylcarbamate (318 mg, 0.81 mmol) and LiAlH₄ (62 mg, 1.62 mmol) in dry THF (30 mL) was refluxed overnight, cooled to room temperature, treated with 13% aqueous NaOH solution (0.1 mL) then water (0.3 mL), stirred for 30 min, filtered through Celite and concentrated in vacuo. The resulting solid was triturated with THF and filtered to give the title compound (20 mg, 7%) as a yellow solid.

Method BC

7-Fluoro-5-methylindole

A solution of chloral hydrate (7.3 g, 44 mmol), sodium sulphate decahydrate (52 g, 160 mmol) and H₂O (100 mL) was added slowly to a stirred solution of 2-fluoro-4-methylamine (5.0 g, 40 mmol), hydroxylamine hydrochloride (11.1 g, 160 mmol) and conc. HCl (3 mL) in H₂O (50 mL). The reaction mixture was refluxed for 1 h, stirred at room temperature for 5 h, filtered and the resulting solid crystallised from MeOH/H₂O to yield brown crystals (1.53 g). This material was added in small portions with stirring to conc. sulphuric acid (20 mL) at 70° C., stirred for 1 h, then added slowly with rapid stirring to ice/H₂O (200 mL), extracted twice with EtOAc (2×25 mL) and the combined organic phase dried (MgSO₄) and concentrated in vacuo to give 7-fluoro-5-methylisatin (1.68 g, 24%) as a dark red gum.

A solution of 7-fluoro-5-methylisatin (1.68 g, 9.43 mmol) in dry THF (50 mL) was added slowly to an ice cold, stirred suspension of LiAlH₄ (1.18 g, 31 mmol) in dry THF (50 mL), refluxed for 2 h, cooled to room temperature then treated sequentially with H₂O (1.2 mL), 15% NaOH (1.2 mL) and H₂O (3 mL). The solution was filtered through a pad of Celite, washing the filter cake thoroughly with TFH, the deep blue filtrate was concentrated in vacuo and purified by chromatography [SiO₂; iso-Hexane:EtOAc (9:1)] to give the title compound (480 mg, 41%) as a pale blue oil; NMR δ_(H) (CDCl₃) 8.19 (1H, br s), 7.21–7.16 (2H, m), 6.74 (1H, d, J 12.0 Hz), 6.51–6.46 (1H, m) and 2.42 (3H, s).

Method BE

3-(7-Fluoro-5-indolyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine Example 246

A stirred suspension of 7-(2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyriridine-5-amine (303 mg, 1.5 mmol) in DMF (2 mL) was treated with NaH (60% dispersion in oil, 60 mg, 1.5 mmol), stirred for 10 min, treated slowly with a solution of tert-butyl 5-bromomethyl-7-fluoroindole-1-carboxylate (460 mg, 1.5 mmol) in DMF (1 mL), stirred for 2 h then the mixture was purified directly by chromatography [SiO₂; iso-hexane:EtOAc (2:1)] to give the BOC protected product (180 mg, 0.417 mmol) as a pale green solid. This material was dissolved in MeOH (5 mL), treated with sodium methoxide (113 mg, 2 mmol), refluxed for 4 h, cooled to room temperature, diluted with H₂O and filtered to give the title compound (118 mg, 81%) as a cream solid.

Method BF

3-(3-(4-Fluorobenzylamino)benzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine Example 252

A suspension of 3-(3-aminobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (200 mg, 0.65 mmol) and 4A molecular sieves in THF (10 mL) was treated with 4-fluorobenzaldehyde (0.04 mL, 0.37 mmol), heated to 40° C. for 3 h, cooled to room temperature, treated sodium triacetoxyborohydride (400 mg, 1.89 mmol) and acetic acid (0.1 mL) and stirred for 15 minutes. The reaction was quenched by addition of sat. NaHCO₃ (5 mL), extracted with EtOAc (2×5 mL) and the combined organic phase dried (MgSO₄), concentrated in vacuo and purified by chromatography [(SiO₂; EtOAc:Heptane (1:2)] to give the title compound (60 mg, 44%) as a white solid.

Method BG

2-(2-Methoxyethyl)-6-(triphenylmethoxy)methylpyridine

A stirred solution of (methoxymethyl)triphenylphosphonium chloride (2.79 g, 8.13 mmol) in THF (50 mL) at 0° C. was treated dropwise with n-BuLi (1.6-M in hexanes, 5.08 mL, 8.13 mmol), stirred for 1 h, treated with a solution of 6-(triphenylmethoxy)methylpyridine-2-carboxaldehyde (1.54 g, 4.06 mmol) in THF (15 mL) and allowed to warm to room temperature overnight. The reaction was treated with saturated NH₄Cl solution (5 mL), diluted with water (50 mL), extracted with EtOAc (2×50 mL) and the combined organic phase diluted with iso-hexane (50 mL), dried (MgSO₄), filtered through silica and concentrated in vacuo to give 2-(2-methoxyethenyl)-6-(triphenylmethoxy)methylpyridine (1.58 g) as a yellow oil. A solution of this crude alkene and 10% Pd/C (216 mg, 0.203 mmol) in EtOAc (50 mL) was stirred under a hydrogen atmosphere for 16 h, filtered through Celite and concentrated in vacuo to give the title compound (1.08 g, 65%) as a yellow oil; NMR δ_(H) (400 MHz, CDCl₃) 7.67–7.64 (1H, m), 7.52–7.49 (6H, m), 7.32–7.21 (10H, m), 7.09–7.07 (1H, m), 4.34 (2H, s), 3.69 (2H, t, J 6.5 Hz), 3.32 (3H, s) and 2.98 (2H, t, J 6.5 Hz); M/Z 410 (M+H)⁺.

Method BH

2-Bromomethyl-6-(2-methoxyethyl)pyridine

A solution of 2-(2-methoxyethyl)-6-(triphenylmethoxy)methylpyridine (1.08 g, 2.64 mmol) in 4-M HCl in dioxan (10 mL, 40.0 mmol) was stirred for 4 h and concentrated in vacuo. The residue was partitioned between dichloromethane (15 mL) and saturated NaHCO₃ solution (15 mL), the aqueous phase was extracted with dichloromethane (10 mL) and the combined organic phase was dried (MgSO₄) and concentrated in vacuo to give 6-(2-methoxyethyl)pyridine-2-methanol. A solution of this product in dichloromethane (40 mL) at 0° C. was treated with triphenylphosphine (830 mg, 3.16 mmol) followed portion wise by carbon tetrabromide (1.31 g, 3.96 mmol), stirred for 1 h, concentrated in vacuo and purified by chromatography [SiO₂; isohexane:EtOAc (4:1)] to give the title compound (303 mg, 50%) as a yellow oil; NMR δ_(H) (400 MHz, CDCl₃) 7.60 (1H, t, J 7.5 Hz), 7.28 (1H, d, J 7.5 Hz), 7.13 (1H, d, J 7.5 Hz), 4.53 (2H, s), 3.76 (2H, t, J 6.5 Hz), 3.35 (3H, s) and 3.05 (2H, t, J 6.5 Hz).

Experimental data for Examples 1–274 are Provided in Table 2.

HPLC is carried out using the following conditions: Column. Waters Xterra RP 18 (50×4.6 mm); Particle size 5 μM; Mobile phase MeOH: 10 mM aq NH₄OAc (pH 7 buffer); Gradient 50:50 isocratic for 1 min. then linear gradient 50:50 to 80:20 over 5 min. then 80:20 isocratic for 3 min.; Flow rate 2.0 mL/min.; Detection wavelength λ=230 nM. Retention times are provided in Table 2.

TABLE 2 Example Method Yield(%) Physical Data 1 A 65 IR ν_(max)(Nujol)/cm⁻¹ 3403, 3329, 3134, 2925, 1656, 1634, 1582, 1565, 1463 and 1377; NMR δ_(H)(400 MHz, DMSO) 6.83–6.87(1H, m), 7.12(2H, s), 7.89(1H, d, J 3.1 Hz), 8.09–8.10(1H, m), 15.52(1H, s); M/Z 203(M+H)⁺. 2 B 11 IR ν_(max)(Nujol)/cm⁻¹ 2924, 2854, 1612, 1587, 1526, 1489, 1456, 1372, 1221 and 753; NMR δ_(H)(400 MHz, DMSO) 4.98(2H, s), 5.14(2H, s), 5.71(2H, s), 6.85–6.87 (1H, m), 7.00–7.14(3H, m), 7.14–7.46(9H, m), 7.89(1H, d, J 3.5 Hz), 8.16(1H, d<J 1.0 Hz); Anal. Calcd for C₂₉H₂₁F₃N₆O. 0.25 H₂O: C, 65.59; H, 4.08; N, 15.83. Found: C, 65.46; H, 4.03; N, 15.76. 3 B 22 IR ν_(max)(Nujol)/cm⁻¹ 3480, 3312, 3195, 3118, 2925, 2854, 1652, 1609, 1581, 1487, 1456, 1436, 1027 and 759; NMR δ_(H)(400 MHz, DMSO) 5.60(2H, s), 6.84–6.86 (1H, m), 7.15–7.29(3H, m), 7.32–7.43(3H, m), 7.89(1H, d, J 2.9 Hz), 8.12(1H, s). 4 B 9 mp 221.0–221.1° C.; IR ν_(max)(Nujol)/cm⁻¹ 3470, 3310, 3191, 3144, 2924, 2854, 1642, 1610, 1521, 1463 and 1354; NMR δ_(H)(400 MHz, DMSO) 5.85(2H, s), 6.87(1H, s), 7.37(2H, s), 7.63–7.73(2H, m), 7.91(1H, d, J 2.8 Hz), 8.13(1H, s), 8.18(1H, s), 8.20(1H, s). Anal. Calcd for C₁₅H₁₁N₇O₃: C, 50.57; H, 3.11; N, 27.52. Found: C, 50.99; H, 3.23; N, 27.21. 5 C 92 mp 259.8–259.9° C.; IR ν_(max)(Nujol)/cm⁻¹ 3452, 3367, 3318, 3185, 3142, 2922, 1651, 1602, 1514, 1463 and 1377; NMR δ_(H)(400 MHz, DMSO) 5.09(2H, s), 5.49(2H, s), 6.35(1H, s), 6.41(1H, d, J 7.5 Hz), 6.45(1H, d, J 8.0 Hz), 6.85–6.86 (1H, m), 6.96(1H, t, J 8.0 Hz), 7.30(2H, s), 7.90(1H, d, J 3.5 Hz), 8.11 (1H, s). Anal. Calcd for C₁₅H₁₃N₇O: C, 56.63; H, 4.50; N, 30.82. Found: C, 56.82; H, 4.25; N, 30.57. 6 B 21 IR ν_(max)(Nujol)/cm⁻¹ 3405, 3328, 3211, 3155, 2925, 2854, 1719, 1603, 1577, 1463, 1023 and 731; NMR δ_(H)(400 MHz, DMSO) 3.84(3H, s), 5.76(2H, s), 6.85–6.87 (1H, m), 7.33–7.38(2H, s), 7.50–7.59(2H, m), 7.89–7.92(3H, s), 8.12–8.13 (1H, m); Anal. Calcd for C₁₇H₁₄N₆O₃.0.25 H₂O: C, 57.54; H, 4.12; N, 23.68. Found: C, 57.42; H, 3.75; N, 23.37. 7 B 27 IR ν_(max)(Nujol)/cm⁻¹ 3506, 3309, 3189, 3131, 2925, 2854, 1635, 1606, 1580, 1502, 1417, 1204, 1025 and 762; NMR δ_(H)(400 MHz, DMSO) 3.70(6H, s), 5.58 (2H, s), 6.44(3H, s), 6.84–6.87(1H, m), 7.34(2H, s), 7.90(1H, d, J 3.5 Hz), 8.11–8.12(1H, m); Anal. Calcd for C₁₇H₂₁₆N₆O₃.0.5 H₂O: C, 56.50; H, 4.74; N, 23.26. Found: C, 56.44; H, 4.56; N, 22.98. 8 B 21 IR ν_(max)(Nujol)/cm⁻¹ 3488, 3314, 3146, 2922, 2853, 1667, 1608, 1583, 1463 and 1378; NMR δ_(H)(400 MHz, DMSO) 5.79(2H, s), 6.84–6.87(1H, m), 7.01(1H, d, J 4.0 Hz), 7.05(1H, d, J 4.0 Hz), 7.38(2H, s), 7.89(1H, d, J 3.5 Hz), 8.11–8.13 (1H, m). 9 D 14 IR ν_(max)(Nujol)/cm⁻¹ 3458, 3299, 3174, 3111, 2923, 1625, 1605, 1463 and 1377; NMR δ_(H)(400 MHz, DMSO) 3.61(3H, s), 5.58(2H, s), 6.84–6.94(3H, m), 7.06–7.11 (1H, d, J 8.5 Hz), 7.19(1H, t, J 8.0 Hz), 7.34(2H, s), 7.64–7.67(2H, m), 7.91(1H, d, J 3.0 Hz), 8.12(1H, s), 10.21(1H, s); Anal. Calcd for C₂₉H₂₁F₃N₆O.0.25 H₂O: C, 65.59; H, 4.08; N, 15.83. Found: C, 65.46; H, 4.03; N, 15.76. 10 E 18 IR ν_(max)(Nujol)/cm⁻¹ 3404, 3313, 3202, 3122, 2923, 2854, 1724, 1639, 1609, 1557, 1456, 1407 and 1379; NMR δ_(H)(400 MHz, DMSO) 4.60(2H, d, J 6.0 Hz), 6.86–6.89(1H, m), 7.25–7.32(1H, m), 7.33–7.44(4H, m), 7.67(2H, s), 7.91 (1H, d, J 3.5 Hz), 8.14–8.16(1H, m), 9.25(1H, t, J 6.0 Hz). 11 B 40 IR ν_(max)(Nujol)/cm⁻¹ 3327, 3207, 2924, 2854, 1650, 1602, 1583, 1566, 1513 and 1487; NMR δ_(H)(400 MHz, DMSO) 3.72(3H, s), 5.63(2H, s), 6.80(1H, d, J 7.5 Hz), 6.85–6.89(3H, m), 7.26(1H, t, J 7.5 Hz), 7.33(2H, s), 7.90(1H, d, J 3.5 Hz), 8.11(1H, s); Anal. Calcd for C₁₆H₁₄N₆O₂.0.25 H₂O: C, 58.80; H, 4.47; N, 25.71. Found: C, 58.90; H, 4.40; N, 25.75. 12 B 21 IR ν_(max)(Nujol)/cm⁻¹ 3374, 3311, 3202, 1636, 1606, 1586, 1530, 1511, 1465, 1439, 1377 and 1343: NMR δ_(H)(400 MHz, DMSO) 6.03(2H, s), 6.86–6.89(1H, m), 6.98(1H, d, J 7.5 Hz), 7.36(2H, s), 7.60–7.73(2H, m), 7.92(1H, d, J 3.5 Hz), 8.14(1H, s), 8.2(1H, d, J 8.0 Hz); Anal. Calcd for C₁₅H₁₁N₇O₃.0.35 H₂O: C, 52.43; H, 3.43; N, 28.54. Found: C, 52.51; H, 3.33; N, 28.21. 13 C 67 IR ν_(max)(Nujol)/cm⁻¹ 3489, 3313, 3191, 1638, 1603, 1505, 1460 and 1378; NMR δ_(H)(400 MHz, DMSO) 5.27(2H, s), 5.47(2H, s), 6.50(1H, t, J 7.5 Hz), 6.67–6.78 (2H, m), 6.86(1H, s), 7.01(1H, t, J 7.0 Hz), 7.36(2H, s), 7.90(1H, d, J 3.0 Hz), 8.12(1H, s). 14 F 35 IR ν_(max)(Nujol)/cm⁻¹ 3447, 3327, 3205, 2922, 2853, 1725, 1652, 1611 and 1458; NMR δ_(H)(400 MHz, DMSO) 8.13(1H, d, J 1.0 Hz), 7.90(1H, d, J 3.5 Hz), 7.38 (2H, s), 6.87–6.85(1H, m), 5.40(2H, s), 4.18(2H, q, J 7.0 Hz) and 1.21(3H, t, J 7.0 Hz); Anal. Calcd for C₁₂H₁₂N₆O₂+0.2 H₂O: C, 49.38; H, 4.28, N, 28.79. Found: C, 49.25; H, 4.09; N, 28.47. 15 B 15 IR ν_(max)(Nujol)/cm⁻¹ 3490, 3307, 3189, 2230, 1959, 1728, 1642, 1611, 1583, 1565, 1463, 1377, 1283, 1234, 1030 and 761; NMR δ_(H)(400 MHz, DMSO) 5.75 (2H, s), 6.82–6.89(1H, m), 7.35(2H, s), 7.57–7.59(2H, m), 7.79–7.81(2H, m), 7.91(1H, d, J 3.5 Hz), 8.12(1H, s). 16 B 6 IR ν_(max)(Nujol)/cm⁻¹ 3309, 3184, 2726, 1639, 1608, 1585, 1456, 1377, 1026, 1002, 953 and 750; NMR δ_(H)(4.00 MHz, DMSO) 2.22(2H, quin, J 7.0 Hz), 2.67 (2H, t, J 7.0 Hz), 4.45(2H, t, J 7.0 Hz), 6.83–6.88(1H, m), 7.23–7.35(3H, m), 7.66(1H, dt, J 8.0, 2.0 Hz), 7.89(1H, dd, J 3.5, 1.0 Hz), 8.10–8.13(1H, m); Anal. calcd for C₁₆H₁₅N₇O.0.6 H₂O: C, 57.86; H, 4.92; N, 29.52. Found: C, 57.58; H, 4.53; N, 29.66. 17 B 7 IR ν_(max)(Nujol)/cm⁻¹ 3379, 3336, 3208, 1655, 1604, 1513, 1456, 1325, 11687, 1124, 1025 and 755; NMR δ_(H)(400 MHz, DMSO) 5.79(2H, s), 6.83–6.88(1H, m), 7.36(2H, s), 7.53(1H, d, J 7.5 Hz), 7.60(1H, t, J 7.5 Hz), 7.67–7.76(2H, m), 7.91(1H, d, J 3.5 Hz), 8.13(1H, s); Anal. Calcd. for C₁₆H₁₁F₃N₆O: C, 53.34; H, 3.08; N, 23.31. Found: C, 53.38; H, 3.18; N, 23.15. 18 G 100 IR ν_(max)(Nujol)/cm⁻¹ 3451, 3206, 2361, 2261, 1655, 1604, 1459, 1378, 1195, 1028 and 774; NMR δ_(H)(400 MHz, DMSO) 5.57(2H, s), 6.57–6.63(1H, m), 6.65–6.74(2H, m), 6.83–6.88(1H, m), 7.14(1H, t, J 7.5 Hz), 7.91(1H, d, J 3.0 Hz), 8.12(1H, d, J 1.0 Hz). 19 J 77 mp 291.8–292.0° C.; IR ν_(max)(DR)/cm⁻¹ 3436, 3178, 1651, 1615, 1398, 1226, 1029 and 977; NMR δ_(H)(400 MHz, DMSO) 15.5–15.3(1H, br s), 7.84(1H, d, J 3.5 Hz), 7.07(2H, br s), 6.48(1H, dd, J 3.5, J 1.0 Hz), 2.44(3H, s). 20 B 47 mp 213.5.–213.7° C.; IR ν_(max)(DR)/cm⁻¹ 3300, 3218, 3098, 2957, 2927, 2744, 2368, 1645, 1602, 1570, 1537, 1508, 1490, 1438, 1328 and 1233; NMR δ_(H)(400 MHz, DMSO) 7.86(1H, d, J 3.0 Hz), 7.43–736(1H, m), 7.31(2H, br s), 7.28–7.15 (3H, m), 6.50(1H, dd, J 1.0, J 3.5 Hz), 5.68(2H, s) and 2.45(3H, s). 21 K 99 IR ν_(max)(DR)/cm⁻¹ 3151, 2360, 1654, 1182, 998, 824, 681, and 572; NMR δ_(H) (400 MHz, DMSO) 10.28(1H, d, J 2.0 Hz) and 9.73(1H, d, J 2.5 Hz) 22 A 8 IR ν_(max)(DR)/cm⁻¹ 3479, 3289, 3169, 1597, 1502, 1226, 1119, 999, 880 and 757; NMR δ_(H)(400 MHz, DMSO) 9.43(1H, s), 9.25(1H, s), 7.48–7.34(3H, m) 7.30–7.22 (2H, m), 7.21–7.15(1H, m) and 5.72(2H, s). 23 B 20 mp 187.3–187.7° C.; IR ν_(max)(DR)/cm⁻¹ 3993, 3489, 3319, 3197, 2951, 2725, 2353, 1954, 1719, 1633, 1604, 1503, 1420, 1232, 1032 and 740; NMR δ_(H)(400 MHz, DMSO) 2.27(3H, s) 5.62(2H, s), 6.82–6.88(1H, m), 7.02–7.16(3H, m), 7.24(1H, t, J 7.5 Hz), 7.33(2H, s), 7.90(1H, d, J 3.5 Hz) 8.12(1H, s). 24 N 46 mp 196.9–197.1° C.; IR ν_(max)(DR)/cm⁻¹ 3448, 3321, 3200, 1649, 1616, 1509, 1488; NMR δ_(H)(400 MHz, DMSO) 8.49–8.47(1H, m), 8.12–8.11(1H, m), 7.91 (1H, d, J 3.5 Hz), 7.81–7.77(1H, m), 7.34–7.30(1H, m), 7.27(2H, br s), 7.24 (1H, d, J 8.0 Hz), 6.86–6.85(1H, m), 5.77(2H, s). 25 N 50 IR ν_(max)(DR)/cm⁻¹ 3326, 3211, 2956, 2856, 1641, 1612, 1507, 1491; NMR δ_(H) (400 MHz, CDCl₃) 8.77–8.76(1H, m), 8.58–8.56(1H, m), 8.08(1H, d, J 3.5 Hz), 7.78(1H, m), 7.75–7.72(1H, m), 7.29–7.25(1H, m), 6.71–6.69(1H, m), 5.68(2H, s), 5.37(2H, br s); Anal. Calcd for C₁₄H₁₁N₇O.0.2 H₂O.0.4 C₄H₃O₂: C, 56.41; H, 4.43, N, 29.52. Found: C, 56.10; H, 4.33; N, 29.52. 26 O 85 mp 291.0–291.1° C.; IR ν_(max)(Nujol)/cm⁻¹ 3401, 3317, 3205, 2995, 1714, 1646, 1615, 1587, 1483 and 1247; NMR δ_(H)(400 MHz, DMSO) 13.58–13.31(1H, s), 8.12(1H, s), 7.91(1H, d, J 3.5 Hz), 7.36(2H, s), 6.87–6.86(1H, m) and 5.29 (2H, s); Anal. Calcd for C₁₀H₈N₆O₃.0.6 H₂O: C, 44.32; H, 3.42, N, 31.01. Found: C, 44.26; H, 3.07; N, 30.74. 27 B 19 mp 209.9–210.1° C.; IR ν_(max)(DR)/cm⁻¹ 3504, 3312, 3201, 2948, 1611, 1503, 1435, 1279, 1220, 1025 and 755; NMR δ_(H)(400 MHz, DMSO) 5.69(2H, s), 6.82–6.87 (1H, m), 7.19–7.25(1H, m), 7.33(2H, s), 7.37–7.40(3H, m), 7.90(1H, d, J 3.5 Hz), 8.10–8.13(1H, m). Anal. Calcd for C₁₅H₁₁N₆OCl.0.2 H₂O: C, 54.54; H, 3.48; N, 25.44. Found: C, 54.69; H, 3.33; N, 25.09. 28 K 40 IR ν_(max)(DR)/cm⁻¹ 3282, 2852, 1630, 1368, 1120, 871 and 618; NMR δ_(H)(400 MHz, DMSO) 7.94(1H, d, J 2.5 Hz), 7.45–7.36(2H, m), 7.29–7.22(2H, m), 7.21–7.16(1H, m) and 5.71(2H, s). 29 B 8 IR ν_(max)(DR)/cm⁻¹ 3999, 3483, 3438, 3310, 3207, 2950, 2732, 2452, 1846, 1657, 1486, 1312, 1030 and 754; NMR δ_(H)(400 MHz, DMSO) 4.02(3H, s), 6.81–6.88 (1H, m), 7.25(2H, s), 7.88(1H, d, J 3.5 Hz), 8.09–8.11(1H, m). 30 P 39 IR ν_(max)(Nujol)/cm⁻¹ 3500–3200, 2946, 2835, 1700 and 1523; NMR δ_(H)(400 MHz, DMSO) 8.11(1H, s), 7.89(1H, d, J 3.5 Hz), 7.69(1H, s), 7.34(1H, s), 7.26(2H, s), 6.87–6.84(1H, m) and 5.08(2H, s). 31 P 48 IR ν_(max)(Nujol)/cm⁻¹ 3457, 3313, 1666, 1617, 1523 and 1442; NMR δ_(H)(400 MHz, DMSO) 10.68(1H, s), 8.12(1H, s), 7.91(1H, d, J 3.5 Hz), 7.75(1H, s), 7.45(1H, d, J 8.0 Hz), 7.37(1H, t, J 8.0 Hz), 7.30(2H, s), 7.15(1H, d, J 8.0 Hz), 6.88–6.84(1H, m and 5.39(2H, s); Anal. Calcd for C₁₆H₁₂N₇O₂Cl.0.8 H₂O: C, 50.02; H, 3.57, N, 25.27. Found: C, 50.15; H, 3.48; N, 25.12. 32 N 76 mp 191.4–192.0° C.; IR ν_(max)(DR)/cm⁻¹ 3511, 3306, 3194, 2955, 1638, 1476; NMR δ_(H)(400 MHz, DMSO) 8.12–8.11(1H, m), 7.91(1H, dd, J 3.5, 1.0 Hz), 7.66(1H, dd, J 8.0, 7.0 Hz), 7.27(2H, br s), 6.87–6.85(1H, m), 6.73–6.70(2H, m), 5.69(2H, s), 3.68(3H, s); Anal. Calcd for C₁₅H₁₃N₇O₂.0.2 C₄H₈O₂: C, 55.66; H, 4.32, N, 28.76. Found: C, 55.88; H, 4.17; N, 28.59. 33 B 11 mp 204.1–204.2° C.; IR ν_(max)(DR)/cm⁻¹ 3490, 3321, 3200, 2923, 2711, 2490, 1749, 1605, 1502, 1376, 1272, 1034 and 761; NMR δ_(H)(400 MHz, DMSO) 5.83 (2H, s), 6.83–6.86(1H, m), 7.01(1H, dd, J 5.0, 3.5 Hz), 7.16(1H, dd, J 3.5, 1.0 Hz), 7.34(2H, s), 7.48(1H, dd, J 5.0, 1.5 Hz), 7.89(1H, d, J 3.5 Hz), 8.09–8.12 (1H, m). 34 Q 30 mp 225–230° C.; IR ν_(max)(DR)/cm⁻¹ 3520, 3344, 1734, 1611, 1438, 1240, 996, 833 and 761; NMR δ_(H)(400 MHz, DMSO) 8.26(1H, d, J 3.0 Hz), 8.15(1H, d, J 3.0 Hz), 7.50–7.44(2H, br s), 7.42–7.36(1H, m), 7.29–7.21(1H, m), 7.21–7.15 (1H, m) and 5.73(2H, s). 35 H 51 mp 174.0–174.2° C.; IR ν_(max)(DR)/cm⁻¹ 3473, 3317, 3188, 2740, 1736, 1648, 1243, 1004 and 752; NMR δ_(H)(400 MHz, DMSO) 8.68(1H, dd, J 4.0, 1.5 Hz), 7.99(1H, dd, J 5.0, 1.0 Hz), 7.43–7.35(2H, m), 7.31–7.16(5H, m) and 5.71 (2H, s). 36 C 50 mp 231.7–234.0° C.; IR ν_(max)(DR)/cm⁻¹ 3498, 3404, 3309, 2931, 1607, 1539, 1498, 1317, 1101 and 1027; NMR δ_(H)(400 MHz, DMSO) 7.86(1H, dd, J 0.5, 3.5 Hz), 7.24(2H, br s), 6.96(1H, t, J 7.8 Hz), 6.50(1H, dd, J 1.0, 3.5 Hz), 6.48–6.43 (1H, m), 6.43–6.38(1H, m), 6.36(1H, t, J 1.7 Hz), 5.46(2H, s), 5.07(2H, br s) and 2.43(3H, s). 37 N 60 mp 200.8–218.9° C.; NMR δ_(H)(400 MHz, DMSO) 8.12–8.11(1H, m), 7.91 (1H, d, J 3.5 Hz), 7.64(1H, t, J 7.5 Hz), 7.29(2H, br s), 7.18(1H, d, J 7.5 Hz), 6.90(1H, d, J 7.5 Hz), 6.86–6.85(1H, m), 5.70(2H, s) and 2.42(3H, s). 38 Q 35 mp 242.0–242.1° C.; IR ν_(max)(DR)/cm⁻¹ 3513, 3294, 1570, 1234, 999 and 755; NMR δ_(H)(400 MHz, DMSO) 7.96(1H, s), 7.46–7.34(3H, m), 7.30–7.13(3H, m), 5.72(2H, s) and 2.60(3H, s). 39 B 26 IR ν_(max)(Nujol)/cm⁻¹ 3464, 3340, 3189, 2966, 2748, 1692, 1643 and 1605; NMR δ_(H)(400 MHz, DMSO) 8.11–8.09(1H, m), 7.90(1H, d, J 3.5 Hz), 7.33–7.24 (4H, m), 7.19–7.12(2H, m), 7.09(1H, s), 6.86–6.84(1H, m), 5.64(2H, s), 4.07(2H, d, J 6.0 Hz) and 1.33(9H, s). 40 B 12 IR ν_(max)(Nujol)/cm⁻¹ 3474, 3323, 3184, 3006, 2971, 2941, 2837, 1648, 1606 and 1496; NMR δ_(H)(400 MHz, DMSO) 8.13–8.10(1H, m), 7.90(1H, d, J 3.5 Hz), 7.32(2H, s), 6.98(1H, d, J 9.0 Hz), 6.89–6.84(2H, m), 6.48(1H, d, J 3.0 Hz), 5.57(2H, s), 3.76(3H, s) and 3.62(3H, s). 41 B 32 mp 213.8–213.9° C.; IR ν_(max)(DR)/cm⁻¹ 3996, 3654, 3507, 3320, 2930, 2562, 2621, 1944, 1837, 1676, 1428, 1230, 1095, 1026 and 797; NMR δ_(H)(400 MHz, DMSO) 5.65(2H, s), 6.81–6.86(1H, m), 7.16(2H, t, J 8.5 Hz), 7.31(2H, s), 7.44–7.56(1H, m), 7.86(1H, dd, J 3.5, 1.0 Hz), 8.07–8.13(1H, m). Anal. Calcd for C₁₅H₁₀N₆OF₂: C, 54.88; H, 3.07; N, 25.59. Found: C, 54.57; H, 3.05; N, 25.23. 42 Q 29 mp 265.7–26.2° C.; IR ν_(max)(DR)/cm⁻¹ 3491, 3370, 3120, 1614, 1232, 972, 753 and 514; NMR δ_(H)(400 MHz, DMSO) 7.72(1H, s), 7.51–7.43(2H, s), 7.42–7.35 (1H, m), 7.30–7.14(3H, m), 5.73(2H, s) and 2.55(3H, s). 43 H 65 mp 281.1–280.2° C.; IR ν_(max)(DR)/cm⁻¹ 3466, 3326, 1641, 1503, 1379, 1240, 1056, and 825; NMR δ_(H)(400 MHz, DMSO) 15.5(1H, br s), 8.6(1H, dd, J 1.0, 4.0 Hz), 7.96(1H, dd, J 1.0, 5.0 Hz), 7.36(1H, dd, J 4.0, 5.0 Hz) and 7.0(2H, br s). 44 S/T 28 IR ν_(max)(DR)/cm⁻¹ 3255, 1686, 1590, 1458; NMR δ_(H)(400 MHz, DMSO) 11.24 (1H, s), 8.95–8.94(1H, m), 8.37–8.35(1H, m), 8.08–8.07(1H, m), 7.96–7.95 (1H, m), 7.68(1H, d, J 8.0 Hz), 6.85–6.84(1H, m). 45 A 59 mp 190.4–190.8° C.; IR ν_(max)(DR)/cm⁻¹ 3322, 3162, 1665, 1576, 1351, 1119, 1000, 809 and 604; NMR δ_(H)(400 MHz, DMSO) 9.44(1H, s), 9.26(1H, s), 8.24–8.16 (2H, m), 7.95(1H, s), 7.74–7.63(2H, m), 7.45(2H, br s) and 5.87(2H, s). 46 K 99 IR ν_(max)(Nujol)/cm⁻¹ 2967, 1651 and 1463; NMR δ_(H)(400 MHz, DMSO) 8.35–8.24 (3H, s), 8.14–8.11(1H, m), 7.91(1H, d, J 3.5 Hz), 7.47–7.39(2H, m), 7.36–7.31(2H, s), 6.88–6.84(1H, m), 5.67(2H, s) and 3.98(2H, q, J 5.5 Hz); Anal. Calcd for C₁₆H₁₅N₇O.2HCl.0.9 H₂O: C, 46.82; H, 4.62, N, 23.89. Found: C, 47.10; H, 4.40; N, 23.84. 47 B 26 IR ν_(max)(Nujol)/cm⁻¹ 3375, 3194, 2929, 2753, 1732, 1657, 1515, 1400 and 1334; NMR δ_(H)(400 MHz, DMSO) 8.14–8.11(1H, m), 7.90(1H, d, J 3.0 Hz), 7.45–7.29 (6H, m), 6.88–6.84(1H, m), 5.71(2H, s), 2.95(3H, s) and 2.85(3H, s); Anal. Calcd for C₁₈H₁₇N₇O₂.0.5 H₂O: C, 58.06; H, 4.87, N, 26.33. Found: C, 58.16; H, 4.65; N, 26.06. 48 C 49 mp 265.9–266.0° C.; IR ν_(max)(DR)/cm⁻¹ 3448, 3363, 3316, 3189, 1645, 1597, 1511, 1440 and 1103; NMR δ_(H)(400 MHz, DMSO) 8.69(1H, dd, J 1.2, 3.7 Hz), 7.95(1H, dd, J 1.2, 5.0 Hz), 7.38(1H, dd, J 3.9, 5.0 Hz), 7.26(2H, br s), 6.97 (1H, t, J 7.7 Hz), 6.48–6.45(1H, m), 6.44–6.40(1H, m), 6.36(1H, t, J 1.7 Hz), 5.5(2H, s) and 5.11(2H, br s). 49 B 8 IR ν_(max)(Nujol)/cm⁻¹ 3488, 3319, 2952, 1641, 1503 and 1420; NMR δ_(H)(400 MHz, DMSO) 8.49–8.42(1H, m), 8.14(1H, d, J 1.0 Hz), 7.91(1H, d, J 3.5 Hz), 7.78–7.71(2H, m), 7.48–7.32(4H, m), 6.88–6.85(1H, m), 5.72(2H, s) and 2.75(3H, d, J 4.5 Hz). 50 C 60 mp 228.2–228.3° C.; IR ν_(max)(DR)/cm⁻¹ 3441, 3318, 3197, 1738, 1648, 1515, 1122, 1006, 888 and 747; NMR δ_(H)(400 MHz, DMSO) 9.45(1H, s), 9.27(1H, s), 7.44(2H, br s), 6.97(1H, t, J 8.0 Hz), 6.49–6.39(2H, m), 6.35(1H, s), 5.52 (2H, s), and 5.13(2H, s). 51 N 70 mp 182.9–183.1° C.; IR ν_(max)(DR)/cm⁻¹ 3488, 3311, 3199, 2943, 1611, 1504; NMR δ_(H)(400 MHz, DMSO) 8.10(1H, d, J 3.5 Hz), 7.78(1H, m), 7.01(1H, t, J 9.0 Hz), 6.79(1H, dt, J 9.0, 3.5 Hz), 6.75–6.73(1H, m), 6.71–6.70(1H, m), 5.70(2H, s), 5.38(2H, br s), 3.71(3H, s); Anal. Calcd for C₁₆H₁₃N₆O₂F.0.1 H₂O: C, 56.17; H, 3.89, N, 24.56. Found: C, 56.27; H, 3.85; N, 24.22. 52 P 70 mp 263.8–264.0° C.; IR ν_(max)(Nujol)/cm⁻¹ 3305, 3192, 1705, 1635 and 1442; NMR δ_(H)(400 MHz, DMSO) 11.04(1H, s), 8.37(1H, d, J 4.0 Hz), 8.15–8.11 (1H, m), 7.96(1H, d, J 7.0 Hz), 7.91(1H, d, J 3.0 Hz), 7.79(1H, dt, J 7.5, 2.0 Hz), 7.32(2H, s), 7.18–7.11(1H, m), 6.88–6.85(1H, m) and 5.46(2H, s). 53 P 77 mp 256.1–256.4° C.; IR ν_(max)(Nujol)/cm⁻¹ 3454, 3311, 2993, 1664, 1488 and 1439; NMR δ_(H)(400 MHz, DMSO) 8.86(1H, t, J 6.0 Hz), 8.50(1H, d, J 4.5 Hz), 8.12(1H, s), 7.90(1H, d, J 3.5 Hz), 7.79(1H, dt, J 7.5, 1.5 Hz), 7.41–7.25(4H, m), 6.88–6.84(1H, m) and 5.23(2H, s), 4.41(2H, d, J 6.0 Hz); Anal. Calcd for C₁₆H₁₄N₈O₂.0.25 H₂O: C, 54.16; H, 4.12, N, 31.58. Found: C, 54.01; H, 4.03; N, 31.44. 54 P 61 mp 292.2–292.3° C.; IR ν_(max)(Nujol)/cm⁻¹ 3433, 3323, 2975, 2941, 1673 and 1446; NMR δ_(H)(400 MHz, DMSO) 10.50(1H, s), 8.13(1H, s), 7.92(1H, d, J 3.0 Hz), 7.57(2H, d, J 7.5 Hz), 7.37–7.27(4H, m), 7.08(1H, t, J 7.5 Hz), 6.89–6.84 (1H, m) and 5.38(2H, s). 55 B 18 mp 264.5–264.8° C.; IR ν_(max)(DR)/cm⁻¹ 4007, 3489, 3308, 3190, 1649, 1552, 1433, 1349, 1227, 1082, 1030 and 729; NMR δ_(H)(400 MHz, DMSO) 5.99(2H, s), 6.84–6.89(1H, m), 7.39(2H, s), 7.91(1H, d, J 3.5 Hz), 8.11–8.15(1H, m), 8.59(2H, d, J 2.0 Hz), 8.78(1H, t, J 2.0 Hz). 56 B 30 IR ν_(max)(DR)/cm⁻¹ 3508, 3300, 3181, 1611, 1572, 1504, 1420, 1352, 1225 and 1030; NMR δ_(H)(400 MHz, DMSO) 8.22–8.16(2H, m), 7.86(1H, d, J 3.2 Hz), 7.63–7.72(2H, m), 7.35(2H, br s), 6.50(1H, dd, J 1.0, 3.5 Hz), 5.82(2H, s) and 2.45(3H, s). 57 B mp 188.8–188.9° C.; IR ν_(max)(Nujol)/cm⁻¹ 3492, 3302, 3189, 2951, 1635 and 1505; NMR δ_(H)(400 MHz, DMSO) 8.14–8.10(1H, m), 7.90(1H, d, J 3.0 Hz), 7.47–7.32(3H, m), 7.20(1H, q, J 7.0 Hz), 7.05(1H, t, J 7.0 Hz), 6.88–6.83 (1H, m) and 5.75(2H, s). 58 B 15 mp 207.0–207.4° C.; IR ν_(max)(Nujol)/cm⁻¹ 3496, 3229, 3201, 3057, 2965, 2743, 1785 and 1615; NMR δ_(H)(400 MHz, DMSO) 8.13–8.10(1H, m), 7.89(1H, d, J 3.5 Hz), 7.40–7.27(4H, m), 7.08(1H, dt, J 8.5, 3.0 Hz), 6.87–6.84(1H, m) and 5.66(2H, s). 59 B 30 mp 187.9–188.7° C. IRν_(max)(DR)/cm⁻¹ 3338, 3202, 1659, 1607, 1567, 1523, 1457, 1424, 1321, 1204 and 1025; NMR δ_(H)(400 MHz, DMSO) 7.88(1H, d, J 3.5 Hz), 7.65(1H, t, J 7.5 Hz), 7.29(2H, br s), 7.18(1H, d, J 7.5 Hz), 6.89(1H, d, J 8.0 Hz), 6.51(1H, d, J 3.0 Hz), 5.69(2H, s), 2.46(3H, s) and 2.42(3H, s); Anal. Calcd for C₁₆H₁₅N₇O.0.2 H₂O: C, 59.14; H, 4.78, N, 30.17. Found: C, 59.37; H, 4.66; N, 29.86. 60 B 33 mp 209.7–209.8° C.; IR ν_(max)(DR)/cm⁻¹ 3404, 3330, 3226, 3109, 2961, 2926, 2742, 1637, 1601, 1508, and 1474; NMR δ_(H)(400 MHz, DMSO) 7.83(1H, dd, J 0.5, 3.2 Hz), 7.54–7.46(1H, m), 7.3(2H, br s), 7.16(2H, t, J 8.2 Hz), 6.49(1H, dd, J 1.0, 3.5 Hz), 5.63(2H, s) and 2.44(3H, s). 61 B 20 mp 193.8–194.1° C.; IR ν_(max)(DR)/cm⁻¹ 3336, 3218, 2980, 2753, 2432, 1734, 1654, 1611, 1438, 1381, 1331 and 1224; NMR δ_(H)(400 MHz, DMSO) 7.86(1H, d, J 3.0 Hz), 7.49(1H, dd, J 1.5, 5.0 Hz), 7.3(2H, br s), 7.16(1H, dd, J 1.0, 3.5 Hz), 7.0(1H, dd, J3.5, 5.0 Hz), 6.50(1H, dd, J 1.0, 3.5 Hz), 5.82(2H, s) and 2.45(3H, s). 62 B 40 mp 210.4–210.5° C.; IR ν_(max)(DR)/cm⁻¹ 3511, 3300, 3179, 2940, 2740, 2688, 1986, 1832, 1734, 1634, 1500 and 1436; NMR δ_(H)(400 MHz, DMSO) 7.87(1H, d, J 3.5 Hz), 7.40–7.37(3H, m), 7.30(2H, br s), 7.23–7.18(1H, m), 6.51 (1H, dd, J 1.0, 5.1 Hz), 5.68(2H, s) and 2.45(3H, s). 63 N 41 mp 201.1–201.2° C.; IR ν_(max)(DR)/cm⁻¹ 3453, 3317, 3195, 1638, 1599, 1510, 1434; NMR δ_(H)(400 MHz, DMSO) 8.28(1H, d, J 6.0 Hz), 8.12–8.11(1H, m), 7.91(1H, d, J 3.5 Hz), 7.29(2H, br s), 6.91(1H, dd, J 6.0, 2.5 Hz), 6.87–6.85 (2H, m), 5.71(2H, s), 3.81(3H, s). 64 B 9 mp 218.0–218.1° C.; IR ν_(max)(DR)/cm⁻¹ 3999, 3376, 3209, 2916, 2747, 2326, 1957, 1782, 1610, 1515, 1278, 1023 and 763; NMR δ_(H)(400 MHz, DMSO) 2.42 (3H, s), 5.64(2H, s), 6.86(1H, s), 6.91(1H, d, J 7.5 Hz), 7.13(1H, t, J 7.0 Hz), 7.17–7.26(2H, m), 7.32(2H, s), 7.90(1H, d, J 3.5 Hz), 8.12(1H, s). 65 B 25 mp 208.1–208.2° C.; IR ν_(max)(Nujol)/cm⁻¹ 3347, 3199, 2981, 2932, 2764, 2719, 1660 and 1612; NMR δ_(H)(400 MHz, DMSO) 8.14–8.11(1H, m), 7.90(1H, d, J 3.5 Hz), 7.41–7.22(4H, m), 7.15–7.09(1H, m), 6.87–6.83(1H, m) and 5.69 (2H, s); Anal. Calcd for C₁₅H₁₀F₂N₆O.0.5 H₂O: C, 53.42; H, 3.29, N, 24.92. Found: C, 53.72; H, 3.06; N, 24.77. 66 W 25 mp 243.4–243.9° C.; IR ν_(max)(Nujol)/cm⁻¹ 4008, 3483, 3316, 3196, 1734, 1599 and 1505; NMR δ_(H)(400 MHz, DMSO) 8.32(1H, dd, J 9.0, 3.0 Hz), 8.21(1H, d, J 3.0 Hz), 8.12–8.10(1H, m), 7.68(1H, d, J 3.5 Hz), 7.31(1H, d, J 9.0 Hz), 7.00(2H, s), 6.85–6.82(1H, m), 5.94(2H, s) and 3.93(3H, s); Anal. Calcd for C₁₆H₁₃N₇O₄: C, 52.32; H, 3.57, N, 26.68. Found: C, 52.16; H, 3.56; N, 26.67. 67 B 32 mp 252.9–253.0° C.; IR ν_(max)(DR)/cm⁻¹ 3511, 33260, 2945, 1732, 1626, 1573, 1499, 1422, 1327 and 1222; NMR δ_(H)(400 MHz, DMSO) 8.4(1H, d, J 4.5 Hz), 7.87(1H, d, J 3.0 Hz), 7.77–7.71(2H, m) 7.47–7.38(2H, m), 7.3(2H, br s), 6.50(1H, dd, J 1.0, 3.5 Hz), 5.70(2H, s), 2.75(3H, d, J 4.5 Hz) and 2.45(3H, s). 68 R 58 mp 228.1–229.3° C.; IR ν_(max)(Nujol)/cm⁻¹ 3508, 3263, 2990, 2946, 2837, 1646 and 1419; NMR δ_(H)(400 MHz, DMSO) 8.29(1H, t, J 6.0 Hz), 8.14–8.09(1H, m), 7.90(1H, d, J 3.5 Hz), 7.33(2H, s), 7.29(1H, t, J 7.5 Hz), 7.21–7.09(3H, m), 6.88–6.83(1H, m), 5.64(2H, s), 4.20(1H, d, J 6.0 Hz) and 1.83(3H, s); Anal. Calcd for C₁₈H₁₇N₇O₂.0.25 H₂O: C, 58.77; H, 4.79, N, 26.65. Found: C, 58.86; H, 4.54; N, 26.24. 69 X 2 NMR δ_(H)(400 MHz, DMSO) 8.53(1H, s), 7.69(1H, s), 7.58(2H, br s), 7.45–7.36 (1H, m), 7.29–7.22(2H, m), 7.21–7.15(1H, m) and 5.73(2H, s); Retention time 1.14 min. 70 N 39 NMR δ_(H)(400 MHz, DMSO) 8.45(1H, d, J 5.0, 1.0 Hz), 8.13–8.12(1H, m), 7.91(1H, dd, J 3.5, 1.0 Hz), 7.51–7.48(2H, m), 7.31(2H, br s), 6.87–6.85(1H, m), 5.80(2H, s); Retention time 1.75 min. 71 N 65 mp 228.7–228.9° C.; IR ν_(max)(DR)/cm⁻¹ 3408, 3326, 3210, 1648, 1614, 1511; NMR δ_(H)(400 MHz, DMSO) 8.13–8.12(1H, m), 8.02–7.96(1H, m), 7.92(1H, d, J 3.5 Hz), 7.33(2H, br s), 7.20(1H, dd, J 7.5, 2.0 Hz), 7.12(1H, dd, J 8.0, 2.0 Hz), 6.87(1H, dd, J 3.5, 1.0 Hz), 5.75(2H, s); Anal. Calcd for C₁₄H₁₁N₇OF.0.2 H₂O.0.1 C₄H₁₀O₂: C, 53.66; H, 3.57, N, 30.42. Found: C, 53.68; H, 3.44; N, 30.24. 72 B 28 mp 195.4–196.5° C.; IR ν_(max)(DR)/cm⁻¹ 3328, 3210, 2956, 2836, 2740, 1736, 1648, 1608, 1438, 1322 and 1250; NMR δ_(H)(400 MHz, DMSO) 7.87(1H, d, J 3.5 Hz), 7.33–7.25(3H, m), 7.05(1H, d, J 7.5 Hz), 6.88(1H, td, J 1.0, 7.5 Hz), 6.87(1H, dd, J 2.0, 7.5 Hz), 6.50(1H, dd, J 1.0, 3.5 Hz), 5.58(2H, s), 3.83(3H, s) and 2.45(3H, s). 73 B 28 mp 178.7–179.3° C.; IR ν_(max)(DR)/cm⁻¹ 3468, 3346, 3172, 2988, 2747, 2130, 1943, 1696, 1610, 1418, 1330, and 1177; NMR δ_(H)(400 MHz, DMSO) 7.86(1H, d, J 3.01 Hz), 7.34–7.26(4H, m), 7.20–7.10(2H, m) 7.09(1H, s), 6.50(1H, dd, J 1.0, 3.5 Hz), 5.63(2H, s), 4.2(2H, d, J 6.0 Hz), 2.45(2H, s) and 1.34(9H, s). 74 C 40 mp 214.6–215.2° C.; IR ν_(max)(DR)/cm⁻¹ 2877, 1653, 1596, 1523, 1470, 1355, 1284, 1241, 1210 and 1109; NMR δ_(H)(400 MHz, DMSO) 7.87(1H, d, J 3.0 Hz), 7.16(1H, t, J 7.0 Hz), 7.0–6.75(3H, m), 6.51(1H, d, J 3.0 Hz), 5.58(2H, s) and 2.45(3H, s). 75 C 3 NMR δ_(H)(400 MHz, DMSO) 4.74(4H, s), 5.33(2H, s), 5.62(2H, d, J 2.0 Hz), 5.71(1H, t, J 2.0 Hz), 6.83–6.88(1H, m), 7.29(2H, s), 7.91(1H, dd, J 3.5, 1.0 Hz), 8.10–8.12(1H, m); Retention time 2.95 min. 76 K 100 IR ν_(max)(DR)/cm⁻¹ 3011, 1650, 1525, 1468, 1351, 1284 and 1210; NMR δ_(H)(400 MHz, CD₃OD) 8.36(1H, d, J 3.5 Hz), 7.53–7.42(4H, m), 6.72(1H, dd, J 1.0 Hz, 3.5 Hz), 5.76(2H, s), 4.11(2H, s) and 2.61(3H, s). 77 W 25 mp 212.1–214.3° C.; IR ν_(max)(DR)/cm⁻¹ 4007, 3474, 3323, 3199, 2934, 2747, 2105, 1647, 1603, 1492, 1245, 1028 and 754; NMR δ_(H)(400 MHz, DMSO) 3.82 (3H, s), 5.60(2H, s), 6.78–6.93(3H, m), 7.05(1H, d, J 8.5 Hz), 7.24–7.38 (3H, m), 7.90(1H, d, J 3.0 Hz), 8.12(1H, s). 78 B 21 IR ν_(max)(DR)/cm⁻¹ 4002, 3482, 3313, 3201, 2938, 2739, 2339, 2107, 1936, 1731, 1650, 1436, 1253, 1082 and 751; NMR δ_(H)(400 MHz, DMSO) 5.82(2H, s), 6.84–6.88 (1H, m), 7.38(2H, s), 7.58(1H, t, J 9.0 Hz), 7.90(1H, t, J 3.0 Hz), 8.12 (1H, d, J 1.0 Hz), 8.23–8.28(1H, m), 8.29–8.35(1H, m). 79 C 64 mp 308.2–308.3° C.; IR ν_(max)(DR)/cm⁻¹ 4013, 3456, 3322, 3193, 2958, 2745, 2103, 1861, 1653, 1516, 1237, 1026 and 777; NMR δ_(H)(400 MHz, DMSO) 4.95 (2H, s), 5.56(2H, s), 6.15–6.20(1H, m), 6.44–6.51(1H, m), 6.84–6.93(2H, m), 7.34(2H, s), 7.91(1H, d, J 3.0 Hz), 8.12(1H, d, J 1.0 Hz). 80 Y 10 NMR δ_(H)(400 MHz, DMSO) 8.84(1H, br s), 7.46–7.35(2H, m), 7.32–7.14 (4H, m) and 5.72(2H, s); Retention time 0.84 min. 81 B 47 mp 229.3–229.4° C.; IR ν_(max)(DR)/cm⁻¹ 3514, 3292, 3166, 1614, 1503; NMR δ_(H) (400 MHz, DMSO) 7.88–7.84(2H, m), 7.47(1H, d, J 8.0 Hz), 7.31(2H, br s), 7.22(1H, d, J 7.0 Hz), 6.52–6.51(1H, m), 5.75(2H, s), 2.46(3H, s); Anal. Calcd for C₁₅H₁₂N₇OCl.0.1 H₂O: C, 52.44; H, 3.58, N, 28.54. Found: C, 52.62; H, 3.59; N, 28.20. 82 H 36 mp 205.0–205.3° C.; NMR δ_(H)(400 MHz, DMSO) 7.97–7.85(5H, m), 7.46–7.41 (3H, m), 7.32(2H, br s), 7.13(1H, d, J 8.5 Hz), 6.53–6.52(1H, m), 5.85 (2H, s), 2.46(3H, s). 83 C 19 mp 252.8–253.3° C.; NMR δ_(H)(400 MHz, MeOD) 8.21(1H, d, J 3.0 Hz), 7.98 (1H, d, 3.5 Hz), 7.62–7.52(2H, m), 7.37–7.31(2H, m) and 5.81(2H, s); Retention time 0.83 min. 84 C 53 mp 235.8–236.5° C.; IR ν_(max)(DR)/cm⁻¹ 3309, 2836, 2033, 1823, 1651, 1505, 1468, 1354, 1250 and 1209; NMR δ_(H)(400 MHz, CD₃OD) 8.18(1H, d, J 4.0 Hz), 7.47–7.37(3H, m), 6.61(1H, dd, J 1.0, 3.5 Hz), 5.82(2H, s) and 2.57(3H, s). 85 R 72 mp 215.9–217.5° C.; IR ν_(max)(Nujol)/cm⁻¹ 3308, 2955, 2869, 1634, 1505 and 1435; NMR δ_(H)(400 MHz, DMSO) 8.27(1H, t, J 5.5 Hz), 8.13(1H, d, J 1.0 Hz), 7.91(1H, d, J 3.5 Hz), 7.36(2H, s), 7.31(1H, t, J 7.5 Hz), 7.17(2H, t, J 7.5 Hz), 7.09(1H, s), 6.89–6.84(1H, m), 5.64(2H, s), 4.21(2H, d, J 6.0 Hz), 1.93(2H, s) and 0.79(6H, d, J 6.5 Hz). 86 B 51 NMR δ_(H)(400 MHz, DMSO) 8.84(1H, d, J 5.5 Hz), 8.14(1H, d, J 2.0 Hz), 8.08 (1H, dd, J 5.5, 1.0 Hz), 7.89(1H, d, J 5.5 Hz), 7.34(2H, br s), 6.53–6.52(1H, m), 5.98(2H, s), 2.46(3H, s); Retention time 1.85 min. 87 Z 73 NMR δ_(H)(400 MHz, DMSO) 9.10(1H, s), 8.69(1H, s), 8.05(1H, d, J 5.5 Hz), 7.89(1H, d, J 3.0 Hz), 7.32(2H, br s), 6.59–6.57(1H, m), 6.53–6.51(1H, m), 6.37–6.36(1H, m), 5.60(2H, s), 2.46(3H, s); M/Z 339(M+H)⁺; Retention time 0.79 min. 88 B 11 mp 258.8–259.0° C.; IR ν_(max)(DR)/cm⁻¹ 4014, 3316, 3204, 2966, 2746, 2561, 2106, 1962, 1606, 1526, 1436, 1351, 1029 and 758; NMR δ_(H)(400 MHz, DMSO) 2.46(3H, s), 5.79(2H, s), 6.86–6.88(1H, m), 7.23(1H, d, J 7.5 Hz), 7.30–7.50 (3H, m), 7.81(1H, d, J 8.0 Hz), 7.91(1H, d, J 3.5 Hz), 8.13–8.15(1H, m). Anal. Calcd for C₁₆H₁₃N₇O₃: C, 54.70; H, 3.73; N, 27.89. Found: C, 54.70; H, 3.77; N, 27.48. 89 C 57 mp 247.1–247.2° C.; IR ν_(max)(DR)/cm⁻¹ 3322, 1740, 1600, 1240, 1167, 959 and 770; NMR δ_(H)(400 MHz, DMSO) 2.10(3H, s), 4.93(2H, s), 5.56(2H, s), 6.11 (1H, d, J 6.5 Hz), 6.58(1H, d, J 8.0 Hz), 6.80(1H, t, J 7.5 Hz), 6.85–6.87(1H, m), 7.35(2H, s), 7.90(1H, d, J 3.5 Hz), 8.12–8.14(1H, m). 90 C 38 mp 268.5–269.1° C.; IR ν_(max)(DR)/cm⁻¹ 4010, 3451, 3317, 3182, 2957, 2749, 2104, 1844, 1652, 1608, 1487, 1335, 1025 and 764; NMR δ_(H)(400 MHz, DMSO) 1.99(3H, s), 4.89(2H, s), 5.47(2H, s), 6.36–6.43(2H, m), 6.84–6.89(2H, m), 7.35(2H, s), 7.91(1H, d, J 3.5 Hz) 8.12–8.14(1H, m). 91 B 15 mp 284.3–284.5° C.; IR ν_(max)(DR)/cm⁻¹ 3321, 3216, 1612, 1031, 765 and 552; NMR δ_(H)(400 MHz, DMSO) 8.12(1H, d, J 1.0 Hz), 7.88(1H, d, J 3.5 Hz), 7.35 (2H, br s), 6.85(1H, dd, J 3.5, 1.5 Hz), 5.44(2H, s), 2.52(3H, s) and 2.25(3H, s) 92 B 8 mp 267.9–268.5° C.; NMR δ_(H)(400 MHz, DMSO) 2.32(3H, s), 5.69(2H, s), 6.85–6.89(1H, s), 7.04–7.10(1H, m), 7.33–7.54(4H, m), 7.90(1H, d, J 3.5 Hz), 8.13–8.15(1H, m). 93 B 4 IR ν_(max)(Nujol)/cm⁻¹ 3316, 3193, 2926, 2851, 1637, 1508 and 1437; NMR δ_(H) (400 MHz, DMSO) 8.11–8.09(1H, m), 7.89(1H, dd, J 3.5, 1.0 Hz), 7.27(2H, s), 6.86–6.83(1H, m), 4.26(2H, d, J 7.5 Hz), 2.04–1.90(1H, m), 1.72–1.50 (5H, m) and 1.25–0.95(5H, m). 94 B 15 mp 237.8–238.0° C.; NMR δ_(H)(400 MHz, DMSO) 2.49(3H, s), 5.76(2H, s), 6.84–6.88(1H, m), 7.28(1H, dd, J 8.5, 1.5 Hz), 7.30–7.42(3H, m), 7.91(1H, d, J 3.5 Hz), 7.97(1H, d, J 8.5 Hz), 8.11–8.14(1H, m). Anal. Calcd for C₁₆H₁₃N₇O₃.0.1 H₂O: C, 54.42; H, 3.77; N, 27.77. Found: C, 54.73; H, 3.78; N, 27.40. 95 N 32 mp 249.8–250.0° C.; IR ν_(max)(DR)/cm⁻¹ 3437, 3317, 3210, 2964, 2865, 1610, 1508; NMR δ_(H)(400 MHz, DMSO) 8.19–8.17(1H, m), 8.12(1H, m), 7.92–7.91 (1H, m), 7.66–7.63(1H, m), 7.24–7.20(3H, m), 6.86(1H, dd, J 3.5, 1.5 Hz), 5.80(2H, s), 2.44(3H, s). 96 B 4 mp 226.6–226.9° C.; NMR δ_(H)(400 MHz, DMSO) 2.32(3H, s), 5.98(2H, s), 6.84(1H, s), 6.85–6.90(1H, m), 7.35(2H, s), 7.43(1H, d, J 7.5 Hz), 7.91(1H, d, J 7.5 Hz), 8.07–8.15(2H, m). 97 C 63 mp 245.3–246.1° C.; IR ν_(max)(DR)/cm⁻¹ 4010, 3406, 3320, 3198, 2929, 2746, 1608, 1507, 1414, 1285, 1022 and 753; NMR δ_(H)(400 MHz, DMSO) 2.00(3H, s), 4.86(2H, s), 5.42(2H, s), 6.54(1H, d, J 8.0 Hz), 6.82–6.85(1H, m), 6.90 (1H, dd, J 8.0, 2.0 Hz), 6.92–6.95(1H, m), 7.29(2H, s), 7.88(1H, d, J 3.5 Hz), 8.09–8.12(1H, m). Anal. Calcd for C₁₆H₁₅N₇O.0.2 H₂O: C, 59.14; H, 4.78; N, 30.17. Found: C, 59.44; H, 4.74; N, 29.82. 98 O 98 IR ν_(max)(Nujol)/cm⁻¹ 3324, 3206, 1698, 1650 and 1611; NMR δ_(H)(400 MHz, DMSO) 13.56–12.46(1H, s), 8.13–8.11(1H, s), 7.92–7.84(3H, m), 7.56–7.31 (3H, m), 6.87–6.85(1H, m) and 7.74(2H, s). 99 P 66 IR ν_(max)(Nujol)/cm⁻¹ 3324, 1644, 1491 and 1417; NMR δ_(H)(400 MHz, DMSO) 8.12(1H, s), 7.98–7.93(1H, s), 7.91(1H, d, J 3.0 Hz), 7.81(1H, d, J 6.5 Hz), 7.77(1H, s), 7.47–7.29(5H, m), 6.86(1H, s) and 5.77–5.68(2H, m). 100 B 13 mp 285.7–285.9° C.; IR ν_(max)(DR)/cm⁻¹ 3345, 3197, 1664, 1613, 1116, 766 and 600; NMR δ_(H)(400 MHz, DMSO) 8.13–8.02(1H, m) 7.90(1H, d, J 3.5 Hz), 7.37–7.27(3H, m), 6.86(1H, dd, J 3.5, 2.0 Hz), 5.67(2H, s) and 2.52(3H, s). 101 AA 32 mp 279.9–280.3° C.; NMR δ_(H)(400 MHz, DMSO) 8.33(3H, br s), 7.93(1H, d, J 2.0 Hz), 7.51–7.39(2H, m), 7.39–7.31(3H, m), 5.69(2H, s) and 3.98(2H, q, J 5.5 Hz). 102 P 23 IR ν_(max)(Nujol)/cm⁻¹ 3480, 3322, 3202, 283, 1608 and 1506; NMR δ_(H)(400 MHz, DMSO) 8.12(1H, s), 7.90(1H, d, J 3.5 Hz), 7.47–7.25(5H, m), 6.87–6.84 (1H, m), 5.72(2H, s), 3.77–3.61(1H, s), 2.76(3H, s), 1.10(3H, s) and 0.99 (3H, s). 103 P 58 IR ν_(max)(Nujol)/cm⁻¹ 3298, 2972, 1635 and 1418; NMR δ_(H)(400 MHz, DMSO) 8.21(1H, d, J 7.5 Hz), 8.12(1H, s), 7.91(1H, d, J 3.0 Hz), 7.82–7.74(2H, m), 7.48–7.29(4H, m), 6.86(1H, s), 5.71(2H, s), 4.13–4.01(1H, m) and 1.13(6H, d, J 6.5 Hz). 104 C 10 mp 249.9–250.5° C.; NMR δ_(H)(400 MHz, DMSO) 2.07(3H, s), 5.06(2H, s), 5.43(2H, s), 6.60–6.65(2H, m), 6.81–6.89(2H, m), 7.37(2H, s), 7.90(1H, dd, J 3.5, 1.0 Hz), 8.12(1H, d, J 1.0 Hz). Anal. Calcd for C₁₆H₁₅N₇O.0.2H₂O: C, 59.14; H, 4.78; N, 30.17. Found: C, 59.53; H, 4.75; N, 29.87. 105 B 16 mp 263.2–263.5° C.; IR ν_(max)(DR)/cm⁻¹ 3499, 3307, 3192, 2958, 2238, 1610, 1490; NMR δ_(H)(400 MHz, DMSO) 8.73(1H, d, J 5.0 Hz), 8.13–8.12(1H, m), 7.92–7.90(1H, m), 7.85–7.81(2H, m), 7.30(2H, br s), 6.87–6.86(1H, m), 5.87(2H, s). 106 B 16 mp 288.1–288.2° C.; IR ν_(max)(DR)/cm⁻¹ 3324, 3196, 1609, 1489, 1166, 1004, 798 and 550; NMR δ_(H)(400 MHz, DMSO) 8.59(1H, s), 8.44(1H, s), 8.12(1H, s), 7.90(1H, d, J 3.5 Hz), 7.31(2H, br s), 6.86(1H, dd, J 3.5, 1.5 Hz), 5.81(2H, s) and 2.48(3H, s). 107 B 22 mp 276.4–277.4° C.; IR ν_(max)(DR)/cm⁻¹ 3443, 3324, 3202, 1610, 1324, 1229, 1030 and 788; NMR δ_(H)(400 MHz, DMSO) 9.01(1H, dd, J 4.0, 2.0 Hz), 8.45(1H, dd, J 8.5, 2.0 Hz), 8.14–8.12(1H, m), 7.97(1H, d, J 8.0 Hz), 7.93(1H, d, J 3.5 Hz), 7.64(1H, 1H, dd, J 8.5, 4.0 Hz), 7.52(1H, t, J 7.0 Hz), 7.31(2H, br s), 7.15(1H, d, J 7.5 Hz), 6.87(1H, dd, J 3.5, 2.0 Hz) and 6.31(2H, s). 108 B 30 mp 215.0–215.3° C.; IR ν_(max)(DR)/cm⁻¹ 3325, 3198, 1612, 1246, 1026, 727 and 567; NMR δ_(H)(400 MHz, DMSO) 8.14–8.12(1H, m), 7.91(1H, dd, J 3.5, 1.0 Hz), 7.90–7.85(2H, m), 7.52(1H, s), 7.51–7.46(3H, m), 7.36(2H, br s), 6.86 (1H, dd, J 3.5, 1.5 Hz), and 5.81(2H, s). 109 Q 23 mp 289.8–289.9° C.; IR ν_(max)(DR)/cm⁻¹ 3350, 2924, 2863, 1981, 1723, 1618, 1351, 1100, 974, 766 and 524; NMR δ_(H)(400 MHz, DMSO) 8.23–8.16(2H, m), 7.77–7.62(3H, m), 7.49(2H, br s), 5.88(2H, s) and 2.56(3H, s). 110 B 31 mp 247.4–247.5° C.; IR ν_(max)(DR)/cm⁻¹ 3999, 3470, 3316, 3198, 2929, 2744, 2345, 2103, 1924, 1837, 1773, 1649, 1435, 1355, 1237, 1029 and 768; NMR δ_(H) (400 MHz, DMSO) 5.79(2H, s), 6.85–6.87(1H, m), 7.36(2H, s), 7.56(1H, dd, J 8.5, 2.0 Hz), 7.76(1H, d, J 8.0 Hz), 7.91(1H, dd, J 3.5, 1.0 Hz), 8.04(1H, d, J 2.0 Hz), 8.12–8.13(1H, m). Anal. Calcd for C₁₅H₁₀N₇O₃Cl: C, 48.47; H, 2.71; N, 26.36. Found: C, 48.63; H, 2.80; N, 26.22. 111 B 14 mp 244.1–244.6° C.; NMR δ_(H)(400 MHz, DMSO) 5.84(2H, s), 6.85–6.89 (1H, m), 7.37(2H, s), 7.54(1H, dd, J 9.5, 1.5 Hz), 7.84(1H, t, J 1.0 Hz), 7.92 (1H, d, J 3.5 Hz), 8.08(1H, dd, J 9.0, 1.0 Hz), 8.12–8.15(1H, m). Anal. Calcd for C₁₅H₁₀N₈O₂.0.75 C₃H₇NO: C, 53.25; H, 3.95; N, 31.50. Found: C, 53.08; H, 3.79; N, 31.38. 112 B 28 mp 190.4–191.4° C.; IR ν_(max)(DR)/cm⁻¹ 3482, 3308, 3194, 2940, 2880, 1610, 1508; NMR δ_(H)(400 MHz, DMSO) 8.13–8.12(1H, m), 7.92(1H, d, J 3.5 Hz), 7.78(1H, t, J 8.0 Hz), 7.35–7.32(3H, m), 7.04(1H, d, J 7.5 Hz), 6.86(1H, dd, J 3.5, 2.0 Hz), 5.75(2H, s), 4.43(2H, s), 3.33(3H, s). 113 B 39 IR ν_(max)(Nujol) cm⁻¹ 3499, 3316, 3193, 2946, 1651 and 1509; NMR δ_(H)(400 MHz, DMSO) 8.13–8.10(1H, m), 7.90(1H, d, J3.5 Hz), 7.39–7.26(7H, m), 6.87–6.84(1H, m) and 5.67(2H, s); Anal. Calcd for C₁₅H₁₂N₆O.0.75 H₂O: C, 58.91; H, 4.45, N, 27.48. Found: C, 58.84; H, 4.10; N, 27.32. 114 C 67 mp 256.7–257.1° C.; IR ν_(max)(DR)/cm⁻¹ 4003, 3452, 3324, 3203, 2950, 2746, 2102, 1733, 1654, 1516, 1420, 1305, 1221, 1106, 1024 and 761; NMR δ_(H)(400 MHz, DMSO) 5.38(2H, s), 5.51(2H, s), 6.46(1H, dd, J 8.5, 2.5 Hz), 6.58(1H, d, J 2.0 Hz), 6.84–6.87(1H, m), 7.15(1H, d, J 8.0 Hz), 7.32(2H, s), 7.91(1H, dd, J 3.5, 1.0 Hz), 8.11–8.13(1H, m). Anal. Calcd for C₁₅H₁₂N₇OCl.0.3 H₂O: C, 51.90; H, 3.66; N, 28.24. Found: C, 52.12; H, 3.48; N, 27.86. 115 B 12 NMR δ_(H)(400 MHz, DMSO) 8.84(1H, d, J 5.5 Hz), 8.15–8.12(2H, m), 8.08–8.06 (1H, m), 7.92–7.91(1H, m), 7.32(2H, br s), 6.87(1H, dd, J 3.5, 1.5 Hz), 5.99(2H, s); Retention time 1.28 min. 116 Z 87 NMR δ_(H)(400 MHz, DMSO) 9.08(1H, br s), 8.66(1H, br s), 8.13–8.12(1H, m), 8.06–8.04(1H, m), 7.93–7.91(1H, m), 7.32(2H, br s), 6.87–6.86(1H, m), 6.60–6.58(1H, m), 6.38–6.37(1H, m), 5.61(2H, s); M/Z 325(M+H)⁺. 117 B 9 IR ν_(max)(DR)/cm⁻¹ 3491, 3310, 3198, 2976, 1612; NMR δ_(H)(400 MHz, DMSO) 8.14–8.13(1H, m), 7.99–7.98(1H, m), 7.93–7.91(1H, m), 7.80–7.79(1H, m), 7.34(2H, br s), 6.88–6.86(1H, m), 5.90(2H, s), 2.57(3H, s). 118 Z 91 NMR δ_(H)(400 MHz, DMSO) 13.45(1H, br s), 9.50(1H, br s), 8.15–8.14(1H, m), 7.92(1H, d, J 3.5 Hz), 7.39(2H, br s), 6.87–6.86(1H, m), 6.56(1H, br s), 6.15(1H, br s), 5.67(2H, s), 2.39(3H, s); M/Z 339(M+H)⁺. 119 B 15 mp > 230° C.; IR ν_(max)(DR)/cm⁻¹ 3993, 3509, 3314, 3195, 2997, 2950, 2682, 2561, 2101, 1943, 1780, 1613, 1501, 1433, 1345, 1100, 1027, 889 and 780; NMR δ_(H)(400 MHz, DMSO) 6.00(2H, s), 6.85–6.90(1H, m), 7.05(1H, d, J 8.5 Hz), 7.37(2H, s), 7.78(1H, dd, J 8.5, 2.0 Hz), 7.91(1H, d, J 3.5 Hz), 8.14(1H, d, J 1.0 Hz), 8.27(1H, d, J 2.5 Hz). Anal. Calcd for C₁₅H₁₀N₇O₃Cl.0.3 H₂O: C, 47.77; H, 2.83; N, 26.00. Found: C, 47.65; H, 2.71; N, 25.85. 120 C 19 mp 211.4–211.6° C.; IR ν_(max)(DR)/cm⁻¹ 4015, 3325, 3218, 2969, 2878, 2101, 1653, 1508, 1423, 1275, 1023, 834 and 761; NMR δ_(H)(400 MHz, DMSO) 5.45 (2H, s), 5.60(2H, s), 6.51(1H, dd, J 8.0, 2.0 Hz), 6.70–6.79(2H, m), 6.83–6.89 (1H, m), 7.38(2H, s), 7.90(1H, d, J 3.5 Hz), 8.12(1H, s). 121 B 13 mp 292.3–292.4° C.; IR ν_(max)(DR)/cm⁻¹ 3324, 3207, 2098, 1602, 1527, 1352, 1024 and 813; NMR δ_(H)(400 MHz, CDCl3) 8.10(1H, d, J 3.0 Hz), 7.79(1H, d, J 1.5 Hz), 7.64(2H, d, J 8.5 Hz), 7.49(2H, d, J 8.5 Hz), 6.71(1H, dd, J 3.5, 1.5 Hz), 5.71(2H, s) and 5.38(2H, br s). 122 A 50 mp 227.5–228.5° C.; IR ν_(max)(DR)/cm⁻¹, 3265, 1701, 1521, 1480, 1413, 1355, 1309, 1204 and 1147; NMR δ_(H)(400 MHz, DMSO) 8.11(1H, d, J 1.0 Hz), 7.9( 1H, d, J 3.5 Hz), 7.3(2H, br s), 7.04(1H, d, J 2.0 Hz), 6.90( 1H, d, J 8.0 Hz), 6.85(1H, dd, J 1.5, 3.5 Hz), 6.79(1H, dd, J 2.0, 8.0 Hz), 5.57(2H, s), 3.71(3H, s,) and 3.72(3H, s). 123 B 35 mp 214.6–216.2° C.; IR ν_(max)(DR)/cm⁻¹ 3512, 3295, 3173, 2988, 2736, 2415, 1636, 1437, 1340 and 1228; NMR δ_(H)(400 MHz, DMSO) 7.97(1H, d, J 8.5 Hz), 7.87(1H, d, J 3.0 Hz), 7.40(1H, d, J 1.0 Hz), 7.31(2H, br s), 7.27(1H, dd, J 1.5, 8.0 Hz), 6.51(1H, dd, J 1.0, 3.5 Hz), 5.74(2H, s), 2.48(3H, s) and 2.46(3H, s). 124 C 65 mp 215.7–216.7° C.; IR ν_(max)(DR)/cm⁻¹ 3328, 2928, 2424, 2345, 1609 and 1263; NMR δ_(H)(400 MHz, DMSO) 7.85(1H, d, J 3.5 Hz), 7.26(2H, br s), 6.93(1H, d, J 1.5 Hz), 6.89(1H, dd, J 2.0, 8.0 Hz), 6.54(1H, d, J 8.0 Hz), 6.49(1H, J 1.0, 3.5 Hz), 5.40(2H, s), 4.89(2H, br s), 2.45(3H, s) and 2.27(3H, s). 125 B 29 mp 221.5–221.6° C.; IR ν_(max)(DR)/cm⁻¹ 3506, 3294, 3178, 2683, 1613, 1315, 1027 and 697; NMR δ_(H)(400 MHz, DMSO) 8.13–8.11(1H, m), 7.90(1H, d, J 4.5 Hz), 7.38(2H, br s), 6.86(1H, dd, J 3.5, 1.5 Hz), 6.18–6.16(1H, m), 5.70 (2H, s) and 2.36(3H, s). 126 N 26 mp 229.6–230.3° C.; IR ν_(max)(DR)/cm⁻¹ 3317, 3198, 1602, 1499; NMR δ_(H)(400 MHz, DMSO) 8.44–8.43(1H, m), 8.31(1H, d, J 5.0 Hz), 8.14–8.13(1H, m), 7.92(1H, d, J 3.0 Hz), 7.35(2H, br s), 6.88–6.86(1H, m), 6.70(1H, d, J 5.0 Hz), 5.71(2H, s), 2.39(3H, s). 127 B 13 mp 275.0–273.3° C.; IR ν_(max)(DR)/cm⁻¹ 3449, 3310, 3202, 1605, 1487, 1420, 1023, 836, 760 and 551; NMR δ_(H)(400 MHz, DMSO) 8.15–8.11(1H, m), 8.07 (1H, d, J 9.0 Hz), 7.91(1H, d, J 3.5 Hz), 7.68(1H, dd, J 9.0, 6.5 Hz), 7.38–7.29 (3H, m), 6.86(1H, dd, J 3.5, 1.5 Hz) and 6.15(2H, s). 128 B 16 mp 129.1–131.0° C.; IR ν_(max)(DR)/cm⁻¹ 3993, 3470, 3310, 3197, 1610, 1508, 1420, 1239, 1002 and 796; NMR δ_(H)(400 MHz, DMSO) 8.74(1H, d, J 1.5 Hz), 8.61(1H, d, J 2.5 Hz), 8.57–8.54(1H, m), 8.13–8.11(1H, m), 7.91(1H, d, J 3.5 Hz), 7.31(2H, br s), 6.86(1H, dd, J 3.5, 2.0 Hz) and 5.88(2H, s). 129 B 20 mp 266.5–266.7° C.; IR ν_(max)(DR)/cm⁻¹ 4018, 3487, 3310, 3193, 2744, 1636, 1585, 1539, 1507, 1437, 1347, 1266, 1238 and 1196; NMR δ_(H)(400 MHz, DMSO) 8.15(1H, dd, J 2.5, 7.5 Hz), 8.12(1H, d, J 1.0 Hz), 7.90( 1H, d, J 3.5 Hz), 7.73–7.68(1H, m), 7.58(1H, dd, J 11.3, 8.8 Hz), 7.36(2H, br s), 6.88(1H, dd, J 1.5, 3.5 Hz) and 5.78(2H, s). 130 H 32 mp 149.0–149.6° C.; IR ν_(max)(DR)/cm⁻¹ 4072, 3332, 3198, 1654, 1604, 1348, 1237, 1111, 1012, 775, 691 and 570; NMR δ_(H)(400 MHz, DMSO) 8.79–8.70 (2H, m), 8.25–8.14(2H, m), 7.77–7.58(5H, m), 7.38(2H, br s) and 5.87(2H, s). 131 B 22 mp 225.7–225.8° C.; NMR δ_(H)(400 MHz, DMSO) 8.33(1H, d, J 4.5 Hz), 8.13–8.12 (1H, m), 7.92–7.91(1H, m), 7.30(2H, br s), 7.15(1H, d, J 5.0 Hz), 7.07–7.06 (1H, m), 6.86(1H, dd, J 1.5, 3.5 Hz), 5.72(2H, s), 2.28(3H, s); Anal. Calcd for C₁₅H₁₃N₇O.0.7 H₂O: C, 56.31; H, 4.54, N, 30.65. Found: C, 56.57; H, 4.24; N, 30.33. 132 N 10 IR ν_(max)(DR)/cm⁻¹ 3332, 2977, 1694, 1608; NMR δ_(H)(400 MHz, DMSO) 8.41 (1H, d, J 4.5 Hz), 8.14–8.13(1H, m), 7.92(1H, d, J 3.5 Hz), 7.43(1H, t, J 6.0 Hz), 7.33(2H, br s), 7.16(1H, d, J 4.5 Hz), 6.97–6.96(1H, m), 6.87(1H, dd, J 2.0, 3.5 Hz), 5.76(2H, s), 4.10(2H, d, J 6.0 Hz), 1.31(9H, s). 133 B 14 mp 209.7–209.9° C.; IR ν_(max)(Nujol)/cm⁻¹ 3506, 3311, 3196, 2996, 2951, 1637, 1518 and 1283; NMR δ_(H)(400 MHz, DMSO) 8.15–8.12(1H, m), 7.91(1H, dd, J 3.5, 1.0 Hz), 7.84(1H, d, J 8.0 Hz), 7.43(1H, d, J 1.5 Hz), 7.42–7.35(2H, s), 6.88–6.82(2H, m), 5.77(2H, s) and 3.91(3H, s). 134 B 14 mp 240.9–241.1° C. IR ν_(max)(DR)/cm⁻¹ 4010, 3629, 3499, 3313, 3196, 2946, 2733, 2447, 1943, 1638, 1528, 1420, 1351, 1222, 1025 and 960. NMR δ_(H)(400 MHz, DMSO) 5.85(2H, s), 6.84–6.89(1H, m), 7.36(2H, s), 7.50(2H, dt, J 8.5, 2.0 Hz), 7.92(1H, dd, J 3.5, 1.0 Hz), 8.12–8.14(1H, m), 8.22(2H, dt, J 9.0, 2.0 Hz). Anal. Calcd for C₁₅H₁₁N₇O₃.0.6H₂O: C, 51.75; H, 3.53; N, 28.17. Found: C, 52.08; H, 3.22; N, 27.96. 135 B 18 mp 208.6–208.8° C.; IR ν_(max)(DR)/cm⁻¹ 3432, 3304, 3191, 2961, 1616, 1500, 1434; NMR δ_(H)(400 MHz, DMSO) 8.14–8.13(1H, m), 7.93–7.91(1H, m), 7.67 (1H, t, J 7.5 Hz), 7.35(2H, br s), 7.19(1H, d, J 7.5 Hz), 6.90–6.86(2H, m), 5.73 (2H, s), 2.68(2H, q, J 7.5 Hz), 1.14(3H, t, J 7.5 Hz). 136 B 18 mp 172.7–173.2° C.; NMR δ_(H)(400 MHz, DMSO) 8.42(1H, d, J 5.5 Hz), 8.14 (1H, m), 7.92(1H, d, J 3.5 Hz), 7.39(2H, br s), 7.11–7.10(1H, m), 6.97(1H, d, J 5.5 Hz), 6.87(1H, dd, J 2.0, 3.5 Hz), 5.70(2H, s), 2.71(2H, q, J 7.5 Hz), 1.18 (3H, t, J 7.5 Hz). 137 B 13 mp 176.3–176.5° C.; IR ν_(max)(DR)/cm⁻¹ 3452, 3326, 3209, 2973, 1734, 1611, 1328, 1026 and 774; NMR δ_(H)(400 MHz, DMSO) 8.13(1H, d, J 2.5 Hz), 7.90 (1H, d, J 3.5 Hz), 7.72(1H, d, J 3.5 Hz), 7.61(1H, d, J 8.5 Hz), 7.34(2H, br s), 7.19(1H, t, J 8.0 Hz), 6.86(1H, dd, J 3.5, 2.0 Hz), 6.77(1H, d, J 4.0 Hz), 6.75 (1H, d, J 7.5 Hz), 6.07(2H, s) and 1.54(9H, s). 138 B 26 mp 58.5–62.6° C.; IR ν_(max)(DR)/cm⁻¹ 3430, 3315, 3210, 3973, 1718, 1165, 834 and 772; NMR δ_(H)(400 MHz, DMSO) 8.13–8.11(1H, m), 8.03(1H, d, J 8.0 Hz), 7.89(1H, d, J 3.5 Hz), 7.73(1H, d, J 4.0 Hz), 7.39(2H, br s), 7.30(1H, t, J 8.5 Hz), 7.08(1H, d, J 7.0 Hz), 6.91(1H, d, J 4.5 Hz), 6.86(1H, dd, J 3.5, 1.5 Hz), 5.90(2H, s) and 1.62(9H, s). 139 K 85 mp 192.3–193.5° C.; NMR δ_(H)(400 MHz, DMSO) 11.27(1H, br s), 8.12(1H, d, J 2.5 Hz), 7.90(1H, d, J 3.5 Hz), 7.39–7.33(2H, m), 7.04(1H, t, J 8.0 Hz), 6.87–6.83 (2H, m), 6.56–6.52(1H, m) and 5.86(2H, s). 140 B 20 mp 184.0–185.2° C.; IR ν_(max)(DR)/cm⁻¹ 3638, 3462, 3331, 3184, 2976, 1686, 1174, 1026 and 756; NMR δ_(H)(400 MHz, DMSO) 8.13(1H, d, J 1.0 Hz), 7.90 (1H, d, J 3.5 Hz), 7.45–7.31(3H, m), 7.27–7.17(4H, m), 6.86(1H, dd, J 3.5, 2.0 Hz), 5.64(2H, s), 4.08(2H, d, J 6.0 Hz) and 1.37(9H, s). 141 C 45 mp 240.3–240.4° C. IR ν_(max)(DR)/cm⁻¹ 3320, 3198, 2929, 1610, 1505, 1438, 1280, 1233, 1028, 956 and 759; NMR δ_(H)(400 MHz, DMSO) 5.85(2H, s), 6.84–6.89 (1H, m), 7.36(2H, s), 7.50(2H, dt, J 8.5, 2.0 Hz), 7.92(1H, dd, J 3.5, 1.0 Hz), 8.12–8.14(1H, m), 8.22(2H, dt, J 9.0 Hz). 142 B 14 mp 189.0–189.1° C.; IR ν_(max)(DR)/cm⁻¹ 3506, 3304, 3180, 1735, 1609, 1167, 1029 and 766; NMR δ_(H)(400 MHz, DMSO) 8.15–8.11(1H, m), 8.02(1H, d, J 8.5 Hz), 7.91(1H, d, J 3.5 Hz), 7.68(1H, d, J 3.5 Hz), 7.53(1H, s), 7.37(2H, br s), 7.29(1H, dd, J 8.5, 1.5 Hz), 6.86(1H, dd, J 3.5, 2.0 Hz), 6.70(1H, d, J 3.5 Hz), 5.75(2H, s) and 1.61(9H, s). 143 B 18 mp 167.0–167.3° C.; IR ν_(max)(DR)/cm⁻¹ 3650, 3485, 3320, 3194, 2978, 1726, 1168, 953 and 756; NMR δ_(H)(400 MHz, DMSO) 9.00(1H, br s), 8.13(1H, s), 7.91(1H, d, J 3.5 Hz), 7.57(1H, t, J 8.0 Hz), 7.39(2H, br s), 7.16(1H, d, J 11.5 Hz), 7.04(1H, d, J 8.5 Hz), 6.86(1H, dd, J 3.5, 2.0 Hz), 5.64(2H, br s) and 1.44 (9H, s). 144 K 56 mp > 300° C. dec; IR ν_(max)(DR)/cm⁻¹ 2903, 2030, 1606, 1464, 1033, 779 and 589; NMR δ_(H)(400 MHz, DMSO) 8.30(2H, br s), 8.14(1H, s), 7.92(1H, d, J 3.5 Hz), 7.46(2H, d, J 8.0 Hz), 7.32(2H, d, J 8.0 Hz), 6.92–6.84(1H, m), 5.69(2H, s) and 4.04–3.96(2H, m). 145 H 30 IR ν_(max)(DR)/cm⁻¹ 3511, 3292, 3164, 2971, 1609, 1525, 1437, 1354 and 1239; NMR δ_(H)(400 MHz, DMSO) 8.19(2H, m), 7.90(1H, d, J 3.5 Hz), 7.72–7.64 (2H, m), 7.36(2H, br s), 6.53(1H, d, J 3.5 Hz), 5.83(2H, s), 2.80(2H, q, J 7.5 Hz), and 1.27(3H, t, J 7.5 Hz). 146 B 35 mp 180.0–180.5° C.; IR ν_(max)(DR)/cm⁻¹ 3325, 3206, 2976, 1734, 1604, 1341, 1024 and 768; NMR δ_(H)(400 MHz, DMSO) 7.92(1H, d, J 3.0 Hz), 7.84(1H, s), 7.67(1H, d, J 4.0 Hz), 7.62(1H, d, J 8.0 Hz), 7.37(2H, br s), 7.26(1H, d, J 8.0 Hz), 6.87(1H, dd, J 3.5, 1.5 Hz), 6.70(1H, d, J 3.5 Hz), 5.80(2H, s) and 1.51 (9H, s). 147 K 57 mp > 200° C. dec; IR ν_(max)(DR)/cm⁻¹ 2816, 2004, 1660, 1507, 1427, 1277, 1030, 746 and 524; NMR δ_(H)(400 MHz, DMSO) 8.15–8.12(1H, m), 7.91(1H, d, J 3.5 Hz), 7.14(1H, d, J 12.0 Hz), 7.06–6.94(2H, m), 6.86(1H, dd, J 3.5, 2.0 Hz) and 5.57(2H, s). 148 B 43 Mp 259.8–259.9° C. IR ν_(max)(DR)/cm⁻¹ 3382, 3214, 2986, 2731, 2090, 1767, 1730, 1606, 1487, 1372, 1275, 1137, 1029, 873 and 771; NMR δ_(H)(400 MHz, DMSO) 1.49(9H, s), 5.63(2H, s), 6.85–6.86(1H, m), 7.20–7.27(2H, m), 7.40 (2H, s), 7.87(1H, d, J 3.0 Hz), 8.11–8.14(1H, m). 149 K 96 IR ν_(max)(Nujol)/cm⁻¹ 3375, 3061, 1653, 1509 and 1474; NMR δ_(H)(400 MHz, DMSO) 11.15–10.13(1H, s), 8.43–7.36(3H, s), 8.14–8.12(1H, m), 7.89 (1H, dd, J 3.5, 1.0 Hz), 6.87–6.84(1H, m), 6.59–6.51(2H, m) and 5.51(2H, s). 150 C 37 IR ν_(max)(DR)/cm⁻¹ 4043, 3461, 3312, 3198, 2970, 2748, 2438, 1923, 1650, 1514, 1497 and 1324; NMR δ_(H)(400 MHz, DMSO) 7.9(1H, d, J 3.5 Hz), 7.31(2H, br s), 6.97(1H, t, J 8.0 Hz), 6.53(1H, d, J 3.5 Hz), 6.45(1H, dd, J 1.5, 8.0 Hz), 6.40(1H, d, J 7.5 Hz), 6.34(1H, t, J 1.7 Hz), 5.48(2H, s), 5.12(2H, s), 2.80(2H, q, J 7.5 Hz) and 1.27(3H, t, J 7.5 Hz). 151 C 48 mp 251.2–251.5° C.; IR ν_(max)(DR)/cm⁻¹ 3449, 3365, 3314, 3196, 2954, 2742, 1731, 1642, 1598, 1556, 1463 and 1407; NMR δ_(H)(400 MHz, DMSO) 8.76–8.72 (2H, m), 7.67–7.62(3H, m), 7.36(2H, br s), 6.97(1H, t, J 8.0 Hz), 6.46 (1H, dd, J 1.5, 8.0 Hz), 6.43(1H, d, J 7.5 Hz), 6.36(1H, t, J 1.7 Hz), 5.52(2H, s) and 5.13(2H, s). 152 AF 86 mp 298.9–299.0° C.; IR ν_(max)(DR)/cm⁻¹ 3422, 3321, 3105, 3942, 1601, 1351, 1219, 1019 and 762; NMR δ_(H)(400 MHz, DMSO) 11.09(1H, br s), 8.13(1H, s), 7.91(1H, d, J 3.0 Hz), 7.51(1H, d, J 8.5 Hz), 7.43–7.31(3H, m), 7.28(1H, s), 7.00(1H, d, J 8.0 Hz), 6.89–6.83(1H, m), 6.39(1H, s) and 5.73(2H, br s). 153 AF 75 mp 226.8–227.4° C.; IR ν_(max)(DR)/cm⁻¹ 3475, 3320, 2739, 1645, 1506, 1223, 1008 and 778; NMR δ_(H)(400 MHz, DMSO) 11.14(1H, br s), 8.14–8.10(1H, m), 7.90(1H, d, J 3.5 Hz), 7.50(1H, s), 7.40–7.31(4H, m), 7.09(1H, dd, J 8.0, 1.5 Hz), 6.85(1H, dd, J 3.5, 1.5 Hz), 6.43–6.38(1H, m) and 5.70(2H, s). 154 AF 77 mp 295.3–295.5° C.; IR ν_(max)(DR)/cm⁻¹ 3215, 1610, 1005, 758, 650 and 565; NMR δ_(H)(400 MHz, DMSO) 11.36(1H, br s), 8.15–8.11(1H, m), 7.91(1H, d, J 3.5 Hz), 7.51(1H, d, J 8.0 Hz), 7.46(1H, t, J 2.5 Hz), 7.43(2H, br s), 6.92(1H, t, J 7.5 Hz), 6.86(1H, dd, J 3.5, 2.0 Hz), 6.71(1H, d, J 7.0 Hz), 6.53–6.49(1H, m) and 5.93(2H, s). 155 B 35 mp 258.6–258.7° C.; IR ν_(max)(Nujol)/cm⁻¹ 3386, 3206, 1646, 1607 and 1481; NMR δ_(H)(400 MHz, DMSO) 8.33(1H, dd, J 9.0, 4.5 Hz), 8.15(1H, s), 7.92(1H, d, J 3.5 Hz), 7.55–7.47(1H, m), 7.47–7.35(2H, s), 6.93–6.85(2H, m) and 6.03(2H, s). 156 AG 99 mp 274.2–274.3° C.; IR ν_(max)(Nujol)/cm⁻¹ 3482, 3305, 3197, 2963, 1606, 1499 and 1420; NMR δ_(H)(400 MHz, DMSO) 8.12(1H, s), 7.87(1H, d, J 3.0 Hz), 7.37 (2H, s), 6.86–6.77(3H, m), 5.55(2H, s) and 3.79(3H, s); Anal. Calcd for C₁₆H₁₂N₆O₂F₂.0.5 H₂O: C, 52.32; H, 3.57, N, 22.88. Found: C, 52.62; H, 3.31; N, 22.72. 157 B 24 mp 204.2–204.4° C.; NMR δ_(H)(400 MHz, DMSO) 1.41(9H, s), 4.37,(2H, d, J 6.0 Hz), 5.72(2H, s), 6.83(1H, d, J 6.0 Hz), 6.85–6.88(1H, d, J 7.5 Hz), 7.14–7.22 (1H, m), 7.30(2H, d, J 4.0 Hz), 7.36(2H, s), 7.48(1H, t, J 6.0 Hz), 7.91 (1H, d, J 3.5 Hz), 8.12–8.14(1H, m). Anal. Calcd for C₂₁H₂₃N₇O₃: C, 59.85; H, 5.50; N, 23.25. Found: C, 59.69; H, 5.54; N, 22.74. 158 AZ mp > 300° C. dec; IR ν_(max)(DR)/cm⁻¹ 3212, 1607, 1438, 1212, 1029 and 770; NMR δ_(H)(400 MHz, DMSO) 15.74(1H, br s), 8.13(1H, s), 7.91(1H, d, J 3.5 Hz), 7.80(2H, br s), 7.54–7.30(3H, s), 6.86(1H, dd, J 4.0, 2.0 Hz) and 5.85 (2H, s). 159 B 16 Mp 235.9–237.8° C.; NMR δ_(H)(400 MHz, DMSO) 8.15–8.13(1H, m), 7.93–7.91 (1H, d, J 3.5 Hz), 7.84–7.82(1H, d, J 2.5 Hz), 7.80–7.76(1H, dd, J 2.5, 8.5 Hz), 7.43–7.37(2H, s) 7.04–7.00(1H, d, J 8.5 Hz), 6.89–6.86(1H, dd, J 2.0, 3.5 Hz), 5.71–5.69(2H s), and 3.99–3.97(3H s). 160 B 28 mp 277.4–277.9° C.; NMR δ_(H)(400 MHz, DMSO) 9.93(1H, s), 8.15–8.12(1H, m), 7.92(1H, d, J 3.5 Hz), 7.55(1H, d, J 8.0 Hz), 7.38(2H, s), 7.34(1H, s), 7.27 (1H, t, J 8.0 Hz), 6.96(1H, d, J 7.5 Hz), 6.88–6.85(1H, m), 5.63(2H, s) and 1.99(3H, s). 161 K 100 mp > 250° C. dec; IR ν_(max)(DR)/cm⁻¹ 3035, 1968, 1654, 1464, 1354, 1247, 1032 and 746; NMR δ_(H)(400 MHz, DMSO) 4.39(2H, q, J 5.5 Hz), 5.81(2H, s), 6.84–6.89 (1H, m), 7.13(1H, d, J 7.5 Hz), 7.31–7.46(3H, m), 7.55(1H, d, J 7.5 Hz), 7.90(1H, d, J 3.5 Hz), 8.12–8.16(1H, m), 8.44(3H, s). Anal. Calcd for C₁₆H₁₅N₇O.2 HCl.1.5 H₂O: C, 45.62; H, 4.79; N, 23.27. Found: C, 45.63; H, 4.71; N, 23.14. 162 B 14 mp 195.1–195.2° C.; IR ν_(max)(DR)/cm⁻¹ 3490, 3375, 3310, 3199, 2895, 1734, 1609, 1507, 1421, 1228, 1026, 1001 and 760; NMR δ_(H)(400 MHz, DMSO) 2.86 (6H, s), 5.58(2H, s), 6.48(1H, d, J 7.5 Hz), 6.64(1H, dd, J 8.0, 2.0 Hz), 6.72–6.75 (1H, m), 6.84–6.87(1H, m), 7.12(1H, t, J 7.5 Hz), 7.35(2H, s), 7.90(1H, d, J 3.5 Hz) and 8.10–8.14(1H, m). 163 B 20 IR ν_(max)(DR)/cm⁻¹ 3489, 3324, 3199, 2560, 1605, 1235, 1121, 1048 and 762; NMR δ_(H)(400 MHz, DMSO) 8.12(1H, d, J 2.5 Hz), 7.90(1H, d, J 3.5 Hz), 7.44–7.32 (4H, m), 7.16(2H, d, J 9.0 Hz), 6.86(1H, dd, J 3.5, 1.5 Hz) and 5.67(2H, s). 164 B 16 mp 120.1–121.0° C.; IR ν_(max)(DR)/cm⁻¹ 3318, 1772, 1709, 1607, 1462, 1395; NMR δ_(H)(400 MHz, DMSO) 8.15–8.14(1H, m), 7.81(1H, d, J 3.5 Hz), 7.77 (1H, t, J 8.0 Hz), 7.71–7.65(4H, m), 7.33(1H, d, J 8.0 Hz), 7.21(2H, br s), 7.12 (1H, d, J 8.0 Hz), 6.88(1H, dd, J 1.5, 3.5 Hz), 5.68(2H, s), 4.80(2H, s). 165 C 60 mp 259.7–259.8° C.; IR ν_(max)(DR)/cm⁻¹ 3457, 3315, 3183, 2959, 2747, 1734, 1653, 1608, 1518, 1441, 1420 and 1386; NMR δ_(H)(400 MHz, DMSO) 8.12(1H, d, J 1.0 Hz), 7.90(1H, d, J 3.5 Hz), 7.35(2H, br s), 6.93(1H, dd, J 8.0, 11.5 Hz), 6.86(1H, dd, 1.5, J 3.5 Hz), 6.58(1H, dd, J 2.0, J 8.5 Hz) 6.47–6.39(1H, m), 5.49(2H, s) and 5.19(2H, s). 166 B 10 mp 210.3–211.2° C.; NMR δ_(H)(400 MHz, DMSO) 8.15–8.10(1H, m), 7.89(1H, d, J 4.5 Hz), 7.35(2H, br s), 7.18(1H, s), 7.08(1H, d, J 8.0 Hz), 6.85(1H, dd, J 3.5, 1.5 Hz), 6.72(1H, d, J 8.0 Hz), 5.55(1H, s), 4.49(2H, t, J 8.5 Hz) and 3.13 (2H, t, J 8.5 Hz). 167 B 11 IR ν_(max)(Nujol)/cm⁻¹ 3486, 3319, and 1606; NMR δ_(H)(400 MHz, DMSO) 8.15–8.10 (1H, m), 7.92–7.87(1H, d, J 3.5 Hz), 7.64–7.56(1H, m), 7.54–7.47(1H, m), 7.46–7.35(2H, s), 7.32–7.22(1H, t, J 9.5 Hz), 6.88–6.84(1H, dd, J 2.0, 3.5 Hz), and 5.71–5.65(2H s); Anal. Calcd for C₁₅H₁₀N₆OFBr.0.5 H₂O: C, 45.25; H, 2.78; N, 21.11. Found: C, 45.10; H, 2.48; N, 20.69. 168 B 12 Mp 204.0–204.2° C.; IR ν_(max)(Nujol)/cm⁻¹ 3343 and 3208; NMR δ_(H)(400 MHz, DMSO) 8.14–8.12(1H, m), 7.91–7.89(1H, dd, J 1.0, 3.5 Hz), 7.62–7.53(1H, m), 7.45–7.37(2H, s), 7.05–6.97(1H, m), 6.88–6.85(1H, dd, J 2.0, 3.5 Hz), and 5.76–5.74(2H, s). 169 B 11 IR ν_(max)(Nujol)/cm⁻¹ 3490 and 3321; NMR δ_(H)(400 MHz, DMSO) 8.15–8.13 (1H, m), 7.91–7.89(1H, d, J 3.5 Hz), 7.78–7.72(1H, m), 7.67–7.63(1H, dd, J 2.0, 7.0 Hz), 7.46–7.38(2H, s), 7.15–7.08(1H, dd, J 9.0, 10.0 Hz) 6.88–6.85 (1H, dd, J 2.0, 3.5 Hz), and 5.67–5.64(2H, s). 170 B 18 IR ν_(max)(Nujol)/cm⁻¹ 3495 and 3304; NMR δ_(H)(400 MHz, DMSO) 8.14–8.12 (1H, m), 7.90–7.88(1H, dd, J 1.0, 3.5 Hz), 7.64–7.62(1H, dd, J 1.0, 2.0 Hz), 7.43–7.37(2H, s), 6.87–6.84(1H, dd, J 1.5, 3.5 Hz), 6.51–6.48(1H, dd, J 1.0, 3.5 Hz), 6.46–6.44(1H, dd, J 2.0, 3.5 Hz) and 5.67–5.65(2H, s). 171 C 59 mp 219.3° C.; IR ν_(max)(Nujol)/cm⁻¹ 3508, 3421, 3307, 3190, 2949, 1609 and 1506; NMR δ_(H)(400 MHz, DMSO) 8.14(1H, s), 7.91(1H, d, J 3.5 Hz), 7.43(2H, s), 6.92–6.85(2H, m), 6.72(1H, dd, J 8.5, 5.0 Hz), 6.52(1H, dd, J 9.5, 3.0 Hz), 5.47(2H, s) and 5.19(2H, s). 172 B 18 IR ν_(max)(Nujol)/cm⁻¹ 3490, 3304, 3182, 2986, 1779, 1762, 1603, 1345 and 1231; NMR δ_(H)(400 MHz, DMSO) 8.16(1H, d, J 8.5 Hz), 8.15–8.13(1H, m), 7.92 (1H, d, J 3.5 Hz), 7.46(1H, d, J 2.0 Hz), 7.45–7.36(2H, s), 7.32(1H, dd, J 8.5, 1.5 Hz), 6.88–6.86(1H, m), 5.84(2H, s) and 1.47(9H, s). 173 C 78 mp 239.6–239.8° C.; IR ν_(max)(Nujol)/cm⁻¹ 3323, 2936, 2733, 1772, 1734, 1609, 1508 and 1282; NMR δ_(H)(400 MHz, DMSO) 9.07(1H, s), 8.13–8.11(1H, m), 7.89(1H, d, J 3.5 Hz), 7.34(2H, s), 6.87–6.84(1H, m), 6.59–6.50(3H, m), 5.41(2H, s) and 4.57(2H, s). 174 K 81 mp > 200° C.; dec; IR ν_(max)(DR)/cm⁻¹ 3144, 2570, 2004, 1654, 1458, 1369, 1280, 1037 and 760; NMR δ_(H)(400 MHz, DMSO) 7.87(1H, d, J 3.5 Hz), 7.13(1H, d, J 11.5 Hz), 7.05–6.91(2H, m), 6.51(1H, dd, J 3.5, 1.0 Hz), 5.55(2H, s) and 2.45 (3H, s). 175 C 17 mp 279.3–281.3° C.; IR ν_(max)(DR)/cm⁻¹ 3462, 3202, 2952, 1653, 1510, 1462, 1416, 1342, 1293 and 1261; NMR δ_(H)(400 MHz, DMSO) 13.52(1H, br s), 7.97 (1H, br s), 7.31(1H, s), 7.25(2H, br s), 6.96(1H, t, J 7.5 Hz), 6.46(1H, dd, J 1.0, 8.0 Hz), 6.42(1H, d, J 7.0), 6.34(1H, s), 5.50(2H, s) and 5.13(2H, s). 176 K 51 IR ν_(max)(Nujol)/cm⁻¹ 3651, 3488, 3317, 1637, 1507 and 1331; NMR δ_(H)(400 MHz, DMSO) 11.04(1H, s), 8.15–8.13(1H, m), 7.92(1H, dd, J 3.5, 1.0 Hz), 7.87(1H, d, J 8.5 Hz), 7.41(2H, s), 6.88–6.86(1H, m), 6.85–6.81(2H, m) and 5.72(2H, s); Anal. Calcd for C₁₅H₁₁N₇O₄.1.0 H₂O: C, 48.52; H, 3.53, N, 26.24. Found: C, 48.68; H, 3.20; N, 26.24. 177 AL 65 mp 245.9–247.0° C.; IR ν_(max)(DR)/cm⁻¹ 3284, 3194, 1654, 1609, 1523; NMR δ_(H) (400 MHz, DMSO) 8.41(1H, t, J 6.0 Hz), 8.14–8.13(1H, m), 7.92(1H, dd, J 1.0, 3.5 Hz), 7.73(1H, t, J 7.5 Hz), 7.37(2H, br s), 7.21(1H, d, J 7.5 Hz), 6.93 (1H, d, J 7.5 Hz), 6.88–6.86(1H, m), 5.74(2H, s), 4.28(2H, d, J 6.0 Hz), 1.88 (3H, s); Anal. Calcd for C₁₇H₁₆N₈O₂.0.5 H₂O.0.1 C₃H₇NO: C, 54.58; H, 4.69, N, 29.80. Found: C, 54.90; H, 4.43; N, 29.46. 178 R 20 mp 216.7–218.4° C.; IR ν_(max)(DR)/cm⁻¹ 3854, 3143, 2569, 2004, 1654, 1518, 1437, 1279, 1207, 1037 and 868; NMR δ_(H)(400 MHz, DMSO) 1.90(3H, s), 4.48 (2H, d, J 6.0 Hz), 5.73(2H, s), 6.82–6.89(2H, m), 7.15–7.23(1H, m), 7.25–7.46 (4H, m), 7.91(1H, d, J 3.5 Hz), 8.12–8.15(1H, m), 8.39(1H, t, J 5.5 Hz). 179 B 11 Mp 215.8–216.9° C.; IR ν_(max)(Nujol)/cm⁻¹ 3482 and 3305; NMR δ_(H)(400 MHz, DMSO) 8.13–8.11(1H, m), 7.91–7.89(1H, d, J 3.5 Hz), 7.55–7.52(1H, dd, J 3.0, 5.0 Hz), 7.42–7.40(1H, m), 7.39–7.34(2H, s), 7.11–7.08(1H, dd, J 1.5, 5.0 Hz), 6.87–6.85(1H, dd J 1.5, 3.5 Hz) and 5.66–5.64(2H, s); Anal. Calcd for C₁₃H₁₀N₆OS: C, 52.34; H, 3.38, N, 28.16. Found: C, 52.53; H, 3.57; N, 28.22. 180 C 25 mp 278.4–279.9° C.; IR ν_(max)(DR)/cm⁻¹ 3468, 3184, 2967, 1735, 1604, 1436, 1322, 1234 and 1204; NMR δ_(H)(400 MHz, DMSO) 7.87(1H, d, J 3.0 Hz), 7.30 (2H, br s), 6.80(1H, t, J 8.0 Hz), 6.58(1H, dd, J 1.0, 8.0 Hz), 6.51(1H, dd, J 3.0, 1.0 Hz), 6.11(1H, d, J 7.0 Hz), 5.54(2H, s), 4.93(2H, br s), 2.45(3H, s) and 2.1 (3H, s). 181 B 12 IR ν_(max)(Nujol)/cm⁻¹ 3501 and 3316; NMR δ_(H)(400 MHz, DMSO) 8.13–8.11 (1H, m), 7.90–7.87(1H, dd, J 1.0, 3.5 Hz), 7.43–7.32(2H, s), 7.40–7.37(1H, d, J 5.0 Hz), 6.90–6.87(1H, d, J 5.0 Hz), 6.86–6.84(1H, dd, J 2.0, 3.5 Hz), 5.73–5.72(2H, s), and 2.37–2.35(3H, s). 182 AM 30 mp 92.3–92.7° C.; IR ν_(max)(DR)/cm⁻¹ 3124, 3073, 2926, 1609, 1520, 1411; NMR δ_(H)(400 MHz, DMSO) 8.18–8.17(1H, m), 7.93(1H, d, J 3.0 Hz), 7.80(1H, t, J 7.5 Hz), 7.37(1H, d, J 7.5 Hz), 7.19(1H, d, J 7.5 Hz), 6.87(1H, dd, J 1.5, 3.5 Hz), 5.94–5.75(3H, m), 5.78(2H, s), 5.28–5.07(6H, m), 4.48(2H, s), 4.43–4.12 (4H, m), 4.02–3.99(2H, m); Anal. Calcd for C₂₄H₂₅N₇O₂: C, 65.00; H, 5.68, N, 22.10. Found: C, 65.23; H, 5.80; N, 21.60. 183 B 27 mp 152.0–153.5° C.; IR ν_(max)(DR)/cm⁻¹ 3515, 3300, 3183, 2934, 2822, 1631, 1450, 1434; NMR δ_(H)(400 MHz, DMSO) 7.89(1H, d, J 3.0 Hz), 7.79(1H, t, J 7.5 Hz), 7.33(2H, br s), 7.34(1H, d, J 7.5 Hz), 7.02(1H, d, J 7.5 Hz), 6.53–6.51 (1H, m), 5.74(2H, s), 4.43(2H, s), 2.46(3H, s), 3.33(3H, s); Anal. Calcd for C₁₇H₁₇N₇O₂: C, 58.11; H, 4.88, N, 27.89. Found: C, 57.75; H, 4.85; N, 27.59. 184 C 76 mp 219.7–220.4° C.; IR ν_(max)(DR)/cm⁻¹ 3450, 3312, 2920, 2728, 1737, 1638, 1438, 1354, 1326, 1291 and 1234; NMR δ_(H)(400 MHz, DMSO) 7.85(1H, d, J 3.0 Hz), 7.30(2H, br s), 7.01(2H, d, J 8.5 Hz), 6.52–6.47(3H, m), 5.41(2H, s), 5.12(2H, s) and 2.44(3H, s). 185 B 15 mp 155.6–157.1° C.; IR ν_(max)(DR)/cm⁻¹ 3332, 3197, 2857, 1655, 1605, 1525, 1420; NMR δ_(H)(400 MHz, DMSO) 8.14–8.13(1H, m), 7.92(1H, d, J 3.5 Hz), 7.79(1H, t, J 7.5 Hz), 7.37(1H, d, J 7.5 Hz), 7.36(2H, br s), 7.05(1H, d, J 7.5 Hz), 6.88–6.86(1H, m), 5.98–5.86(1H, m), 5.76(2H, s), 5.29–5.24(1H, m), 5.17–5.13(1H, m), 4.48(2H, s), 4.06–4.00(2H, m); Anal. Calcd for C₁₈H₁₇N₇O₂: C, 59.50; H, 4.72, N, 26.97. Found: C, 59.39; H, 4.70; N, 26.99. 186 B 23 mp 149.0–149.3° C.; IR ν_(max)(DR)/cm⁻¹ 3514, 3295, 3168, 2861, 1634, 1502, 1435; NMR δ_(H)(400 MHz, DMSO) 7.88(1H, d, J 3.5 Hz), 7.79(1H, t, J 7.5 Hz), 7.37(1H, d, J 7.5 Hz), 7.33(2H, br s), 7.04(1H, d, J 7.5 Hz), 6.52–6.51(1H, m), 5.96–5.86(1H, m), 5.74(2H, s), 5.30–5.24(1H, m), 5.17–5.13(1H, m), 4.49(2H, s), 4.06–4.00(2H, m), 2.46(3H, s); Anal. Calcd for C₁₉H₁₉N₇O₂.0.2 H₂O: C, 59.90; H, 5.13, N, 25.73. Found: C, 59.71; H, 5.02; N, 25.64. 187 B 20 mp 191.7–191.9° C.; IR ν_(max)(Nujol)/cm⁻¹ 3501, 3307, 3189, 2974, 1611, 1527 and 1338; NMR δ_(H)(400 MHz, DMSO) 8.12–8.15(1H, m), 7.91(1H, d, J 3.5 Hz), 7.76(1H, d, J 8.5 Hz), 7.67(1H, d, J 2.0 Hz), 7.44–7.36(2H, s), 7.16(1H, dd, J 8.5, 2.0 Hz), 6.87–6.85(1H, m), 5.78(2H, s), 3.22(1H, quin, J 6.5 Hz) and 1.22(6H, d J 6.5 Hz). 188 B 32 mp 228.9–229.9° C.; IR ν_(max)(DR)/cm⁻¹ 3461, 3317, 3195, 1606, 1504, 1320, 1026 and 818; NMR δ_(H)(400 MHz, DMSO) 8.16–8.14(1H, m), 7.98(1H, d, J 8.0 Hz), 7.94(1H, d, J 3.5, 1.0 Hz), 7.91(1H, d, J 8.0 Hz), 7.78–7.73(1H, m), 7.64–7.58 (1H, m), 7.36(1H, d, J 8.5 Hz), 7.36(2H, br s), 6.88(1H, dd, J 3.5, 1.5 Hz) and 5.98(2H, s). 189 K 23 NMR δ_(H)(400 MHz, DMSO) 8.14–8.12(1H, m), 7.92–7.89(1H, dd, J 1.0, 3.5 Hz), 7.35–7.31(2H, d, J 8.5 Hz), 7.28–7.16(2H, s), 6.88–6.85(1H, dd, J 1.5, 3.5 Hz), 5.66–5.64(2H, s), and 2.82–2.80(3H, s); M/Z 322(M+H)⁺. 190 B 37 mp 290.2–290.3° C.; IR ν_(max)(DR)/cm⁻¹ 3491, 3338, 3205, 3128, 2936, 1710, 1616, 1490, 1458; NMR δ_(H)(400 MHz, DMSO) 8.13–8.12(1H, m), 7.93(1H, t, J 7.5 Hz), 7.90(1H, dd, J 1.0, 3.5 Hz), 7.84(1H, d, J 7.5 Hz), 7.56(1H, d, J 7.5 Hz), 7.34(2H, br s), 6.86(1H, dd, J 2.0, 3.5 Hz), 6.69(1H, q, J 7.5 Hz), 2.48 (3H, s), 1.98(3H, d, J 7.5 Hz); Anal. Calcd for C₁₇H₁₅N₇O₂: C, 58.45; H, 4.33, N, 28.05. Found: C, 58.26; H, 4.42; N, 27.67. 191 C 16 mp 186.1–189.1° C.; IR ν_(max)(DR)/cm⁻¹ 3458, 1598, 1509, 1460, 1329, 1267 and 1220; NMR δ_(H)(400 MHz, DMSO) 11.73(1H, s), 7.59(1H, s), 7.17(1H, s), 6.97 (1H, t, J 7.8 Hz), 6.95–6.83(2H, br s), 6.45(1H, dd, J 1.5, J 8.0 Hz), 6.40(1H, d, J 8.0 Hz), 6.38–6.31(1H, m), 5.47(2H, s) and 5.13(2H, s). 192 Q 2 NMR δ_(H)(400 MHz, CD₃OD) 8.84(1H, d, J 4.5 Hz), 8.77(1H, d, J 8.0 Hz), 8.33 (1H, t, J 1.7 Hz), 8.2(1H, dd, J 2.0, 8.0 Hz), 8.06(1H, td, J 7.8, 2.0 Hz), 7.81 (1H, d, J 7.5 Hz), 7.65–7.58(2H, m) and 5.88(2H, s); M/Z 349(M+H)⁺; Retention time 1.77 min. 193 B 6 mp 253.6–254.0° C.; IR ν_(max)(DR)/cm⁻¹ 3320, 1611, 1414, 1315, 1255, 1026 and 767; NMR δ_(H)(400 MHz, DMSO) 2.01(3H, s), 5.59(2H, s), 6.84–6.88(1H, m), 7.22(2H, d, J 8.5 Hz), 7.36(2H, s), 7.54(2H, d, J 8.5 Hz) 7.90(1H, d, J 3.5 Hz), 8.11–8.14(1H, m), 9.97(1H, s). 194 B 36 mp 136.5–137.6° C.; IR ν_(max)(Nujol)/cm⁻¹ 3489, 3311, 3195, 2954, 1774 and 1613; NMR δ_(H)(400 MHz, DMSO) 8.24(1H, s), 8.04(1H, d, J 2.0 Hz), 8.00 (1H, d, J 3.5 Hz), 7.96(1H, dd, J 8.5, 2.0 Hz), 7.52–7.44(2H, s), 7.40(1H, d, J 8.5 Hz), 6.99–6.95(1H, m), 5.83(2H, s), 5.54(2H, s), 3.66(2H, t, J 8.0 Hz), 0.93(2H, t, J 8.0 Hz) and 0.00(9H, s); Anal. Calcd for C₂₁H₂₅N₇O₅Si.0.1 H₂O: C, 51.97; H, 5.23, N, 20.20. Found: C, 51.97; H, 5.19; N, 19.86. 195 B 12 IR ν_(max)(Nujol)/cm⁻¹ 3652, 3506, 3307, 3196, 2990, 2878, 1633, 1521 and 1344; NMR δ_(H)(400 MHz, DMSO) 8.14(1H, s), 7.94–7.88(2H, m), 7.46(1H, s), 7.40 (2H, s), 7.23(1H, dd, J 8.5, 2.0 Hz), 6.88–6.85(1H, m), 5.78(2H, s), 2.80(2H, q, 7.5 Hz) and 1.17(3H, t, J 7.5 Hz); Anal. Calcd for C₁₇H₁₅N₇O₃.0.25 H₂O: C, 55.21; H, 4.22, N, 26.51. Found: C, 55.47; H, 4.12; N, 26.25. 196 B 23 mp 178.4–179.0° C.; IR ν_(max)(Nujol)/cm⁻¹ 3469 and 3311; NMR δ_(H)(400 MHz, DMSO) 8.13–8.11(1H, m), 7.90–7.88(1H, dd, J 1.0, 3.5 Hz), 7.37–7.32(2H, s), 7.32–7.29(1H, dd, J 1.5, 5.5 Hz), 6.92–6.89(1H, dd, J 3.5, 5.5 Hz), 6.87–6.84 (2H, m), 4.70–4.64(2H, t, J 7.0 Hz), and 3.53–3.48(2H, t, J 7.0 Hz); Anal. Calcd for C₁₄H₁₂N₆OS: C, 53.84; H, 3.87; N, 26.89. Found: C, 53.98; H, 3.87; N, 26.50. 197 B 22 mp 188.3–188.5° C.; IR ν_(max)(DR)/cm⁻¹ 3324, 3189, 2964, 1649, 1513; NMR δ_(H) (400 MHz, DMSO) 8.14–8.13(1H, m), 7.93(1H, d, J 3.5 Hz), 7.67(1H, t, J 7.5 Hz), 7.34(2H, br s), 7.20(1H, d, J 7.5 Hz), 6.89(1H, d, J 7.5 Hz), 6.87–6.86 (1H, m), 5.75(2H, s), 2.93(1H, sept, J 7.0 Hz), 1.12(6H, d, J 7.0 Hz); Anal. Calcd for C₁₇H₁₇N₇O: C, 60.88; H, 5.11, N, 29.22. Found: C, 61.03; H, 5.13; N, 28.95. 198 B 27 IR ν_(max)(DR)/cm⁻¹ 3466, 3312, 3187, 2958, 2850, 1639, 1511, 1221, 1047, 756 and 599; NMR δ_(H)(400 MHz, DMSO) 8.13(1H, s), 8.09(1H, s), 7.91(1H, d, J 3.0 Hz), 7.72(1H, d, J 8.5 Hz), 7.68(1H, s), 7.42(1H, d, J 8.5 Hz), 7.37(2H, br s), 6.88–6.83(1H, m), 5.82(1H, d, J 9.5 Hz), 5.77(2H, s), 3.90–3.80(1H, m), 3.77–3.64(1H, m), 2.45–2.30(1H, m), 2.10–1.88(2H, m), 1.80–1.63(1H, m), 1.62–1.49(2H, m). 199 B 7 mp 226.5–227.9° C.; IR ν_(max)(DR)/cm⁻¹ 3466, 3316, 3182, 2962, 1645, 1606, 1546, 1514, 1473; NMR δ_(H)(400 MHz, DMSO) 8.14–8.13(1H, m), 7.92(1H, d, J 3.0 Hz), 7.33(2H, br s), 7.07–7.06(1H, m), 6.88–6.86(2H, m), 5.71(2H, s), 2.88(1H, sept, J 7.0 Hz), 2.82(1H, sept, J 7.0 Hz), 1.14(6H, d, J 7.0 Hz), 1.09 (6H, d, J 7.0 Hz). 200 K 99 mp > 300° C. dec; IR ν_(max)(DR)/cm⁻¹ 3100, 1662, 1465, 1281, 1032, 782 and 592; NMR δ_(H)(400 MHz, DMSO) 8.16–8.13(1H, m), 8.07(1H, s), 7.92(1H, d, J 3.5 Hz), 7.68(1H, s), 7.54(1H, d, J 8.5 Hz), 7.35(1H, dd, 8.5, 1.5 Hz), 6.87(1H, dd, J 3.5, 2.0 Hz) and 5.76(1H, s) 201 K 99 IR ν_(max)(Nujol)/cm⁻¹ 2999, 1656, 1530 and 1461; NMR δ_(H)(400 MHz, DMSO) 11.10(1H, s), 8.14(1H, d, J 1.0 Hz), 7.92(1H, d, J 3.5 Hz), 7.72(1H, d, J 2.5 Hz), 7.61(1H, dd, J 8.5, 2.5 Hz), 7.0(1H, d, J 8.5 Hz), 6.86–6.88(1H, m), 5.67 (2H, s) and 5.11–5.16(3H, s). 202 B 32 mp 210.5–211.6° C.; IR ν_(max)(FILM)/cm⁻¹ 3352, 3204, 3001, 1659, 1569, 1510, 1440; NMR δ_(H)(400 MHz, DMSO) 8.14(1H, m), 7.93(1H, d, J 3.5 Hz), 7.76 (1H, t, J 7.5 Hz), 7.43(1H, d, J 7.5 Hz), 7.36(2H, br s), 7.03(1H, d, J 7.5 Hz), 6.87(1H, dd, J 2.0, 3.5 Hz), 6.75(1H, dd, J 10.5, 17.5 Hz), 6.09(1H, dd, J 2.0, 17.5 Hz), 5.78(2H, s), 5.43(1H, dd, J 1.5, 10.5 Hz); Anal. Calcd for C₁₆H₁₃N₇O: C, 60.18; H, 4.10, N, 30.69. Found: C, 60.14; H, 4.20; N, 30.39. 203 AS 12 IR ν_(max)(Nujol)/cm⁻¹ 3514, 3298 and 1761; NMR δ_(H)(400 MHz, DMSO) 8.16–8.15 (1H, m), 7.89–7.86(1H, dd, J 1.0, 3.5 Hz), 7.80–7.40(2H, s), 6.89–6.86 (1H, dd, J 1.5, 3.5 Hz), and 1.66–1.64(9H, s). 204 B 16 mp 143.6–144.5° C.; IR ν_(max)(DR)/cm⁻¹ 3644, 3315, 3195, 2978, 1743, 1608, 1163, 1086 and 746; NMR δ_(H)(400 MHz, DMSO) 8.14–8.10(1H, m), 8.05(1H, d, J 8.0 Hz), 7.88(1H, d, J 3.5 Hz), 7.81(1H, s), 7.66(1H, d, J 7.5 Hz), 7.42 (2H, br s), 7.34(1H, t, J 8.0 Hz), 7.23(1H, t, J 8.0 Hz), 6.85(1H, dd, J 3.5, 2.0 Hz), 5.78(2H, s) and 1.63(9H, s) 205 B 19 IR ν_(max)(DR)/cm⁻¹ 3431, 3325, 3217, 1646, 1504, 1431; NMR δ_(H)(400 MHz, DMSO) 9.87–9.86(1H, m), 8.14(1H, m), 8.05(1H, t, J 8.0 Hz), 7.94–7.92 (1H, m), 7.88(1H, d, J 8.0 Hz), 7.52(1H, d, J 8.0 Hz), 7.38(2H, br s), 6.88–6.87 (1H, m), 5.91(2H, s); Anal. Calcd for C₁₅H₁₁N₇O₂.0.3 H₂O: C, 55.15; H, 3.58, N, 30.01. Found: C, 55.33; H, 3.35; N, 29.64. 206 B 30 IR ν_(max)(film)/cm⁻¹ 3327, 3209, 2987, 1730, 1664, 1390, 1168, 959, 745 and 664; NMR δ_(H)(400 MHz, DMSO) 8.16(1H, s), 8.09(1H, d, J 8.0 Hz), 7.97–7.92 (2H, m), 7.47(1H, d, J 7.5 Hz), 7.44–7.35(2H, br s), 7.31(1H, t, J 7.5 Hz), 7.20 (1H, t, J 7.0 Hz), 6.89(1H, dd, J 3.5, 1.5 Hz), 6.03–5.96(3H, m) and 1.64(9H, s) 207 AF 71 mp 289.1–289.3° C.; IR ν_(max)(DR)/cm⁻¹ 3442, 3317, 3189, 1649, 1607, 1519, 1332, 1118, 1023 and 763; NMR δ_(H)(400 MHz, DMSO) 11.21(1H, br s), 8.13 (1H, s), 7.91(1H, d, J 3.5 Hz), 7.46(1H, d, 8.0 Hz), 7.38(2H, br s), 7.33(1H, d, J 8.0 Hz), 7.06(1H, t, J 8.0 Hz), 6.96(1H, t, J 7.0 Hz), 6.86(1H, dd, J 3.5, 1.5 Hz), 6.31(1H, s) and 5.79(2H, s) 208 B 4 NMR δ_(H)(400 MHz, DMSO) 8.13–8.12(1H, m), 7.91–7.88(1H, dd, J 1.5, 3.5 Hz), 7.46–7.36(2H, s), 6.98–6.96(1H, d, J 3.5 Hz), 6.87–6.84(1H, dd, J 1.5, 3.5 Hz), 6.72–6.69(1H, d, J 3.5 Hz), 5.76–5.74(2H, s), 2.52–2.48(2H, h, J 2.0, 3.5 Hz) and 1.20–1.14(3H, t, J 7.5 Hz); M/Z 327(M+H)⁺. 209 B 17 mp > 250° C.; dec; IR ν_(max)(DR)/cm⁻¹ 3489, 3316, 2919, 1610, 1326, 1037, 862, 760 and 593; NMR δ_(H)(400 MHz, DMSO) 8.13–8.11(1H, m), 7.90(1H, d, J 2.5 Hz), 7.38(2H, br s), 6.92(1H, d, J 2.0 Hz), 6.88(1H, d, J 8.0 Hz), 6.86(1H, dd, J 3.5, 2.0 Hz), 6.79(1H, dd, J 8.0, 1.5 Hz), 6.00(2H, s) and 5.56(2H, s). 210 C 36 IR ν_(max)(DR)/cm⁻¹ 3427, 3318, 3201, 2966, 1605, 1503, 1415, 1281, 1027 and 762; NMR δ_(H)(400 MHz, DMSO) 1.08(3H, t, J 7.0 Hz), 2.39(2H, q, J 7.0 Hz), 4.91(2H, s), 5.44(2H, s), 6.54(1H, d, J 8.0 Hz), 6.80–9.62(2H, m), 6.97(1H, s), 7.34(2H, s), 7.89(1H, s), 8.12(1H, s). Anal. Calcd for C₁₇H₁₇N₇O.0.6 H₂O: C, 58.98; H, 5.30; N, 28.32. Found: C, 59.37; H, 5.02; N, 28.05. 211 AT 13 mp 257.1–257.3° C.; IR ν_(max)(DR)/cm⁻¹ 3491, 3343, 3205, 3131, 2971, 1973, 1691, 1626, 1499, 1437, 1239, 1030 and 764; NMR δ_(H)(400 MHz, DMSO) 6.26 (2H, s), 6.86–6.91(1H, m), 7.33(2H, s), 7.63(2H, t, J 7.5 Hz), 7.77(1H, t, J 7.5 Hz), 7.94(1H, d, J 3.0 Hz), 8.11–8.16(3H, m). 212 R 58 IR ν_(max)(DR)/cm⁻¹ 3321, 1608, 1438, 1304, 1025 and 757; NMR δ_(H)(400 MHz, DMSO) 5.67(2H, s), 6.86–6.88(1H, m), 7.05(1H, d, J 7.5 Hz), 7.20(1H, dd, J 5.0, 3.5 Hz), 7.35(1H, t, J 8.0 Hz), 7.39(2H, s), 7.55–7.58(1H, m), 7.72(1H, d, J 7.5 Hz), 7.85(1H, dd, J 5.0, 1.0 Hz), 7.92(1H, d, J 3.5 Hz), 7.98(1H, dd, J 3.5, 1.0 Hz), 8.12–8.15(1H, m), 10.24(1H, s). 213 AU 29 IR ν_(max)(DR)/cm⁻¹ 3285, 1975, 1625, 1461; NMR δ_(H)(400 MHz, DMSO) 8.14 (1H, m), 7.92(1H, d, J 3.0 Hz), 7.80(1H, t, J 7.5 Hz), 7.44(1H, d, J 7.5 Hz), 6.98(1H, d, J 7.5 Hz), 6.87(1H, dd, J 1.5, 3.5 Hz), 5.75(2H, s), 4.52(2H, s). 214 R 43 IR ν_(max)(DR)/cm⁻¹ 3321, 2956, 1610, 1234, 1027 and 757; NMR δ_(H)(400 MHz, DMSO) 0.99(9H, s), 2.14(2H, s), 5.63(2H, s), 6.85–6.89(1H, m), 6.94(1H, d, J 8.0 Hz), 7.27(1H, t, J 7.5 Hz), 7.33–7.45(3H, m), 7.59(1H, d, J 9.0 Hz), 7.92 (1H, d, J 3.5 Hz), 8.12–8.15(1H, m). 215 R 52 IR ν_(max)(DR)/cm⁻¹ 3510, 3278, 1631, 1425, 1293, 1217, 1024 and 757; NMR δ_(H) (400 MHz, DMSO) 0.71–0.79(4H, m), 1.72(1H, tt, J 5.5, 7.0 Hz), 5.63(2H, s), 6.85–6.89(1H, m), 6.96(1H, d, J 8.0 Hz), 7.27(1H, t, J 7.5 Hz), 7.32–7.45 (3H, m), 7.55(1H, d, J 8.0 Hz), 7.92(1H, dd, J 3.5, 1.0 Hz), 8.12–8.15(1H, m), 10.19(1H, s). Anal. Calcd for C₁₉H₁₇N₇O₂.0.15 H₂O: C, 60.36; H, 4.61; N, 25.93. Found: C, 60.89; H, 4.62; N, 25.54. 216 B 15 mp 178.3–178.5° C.; IR ν_(max)(DR)/cm⁻¹ 3472, 3324, 3194, 2964, 1641, 1598, 1510; NMR δ_(H)(400 MHz, DMSO) 8.14(1H, m), 7.92(1H, dd, J 1.0, 3.5 Hz), 7.66(1H, t, J 8.0 Hz), 7.35(2H, br s), 7.17(1H, d, J 8.0 Hz), 6.90(1H, d, J 8.0 Hz), 6.87(1H, dd, J 2.0, 3.5 Hz), 5.73(2H, s), 2.63(2H, t, J 7.5 Hz), 1.59(2H, sext, J 7.5 Hz), 0.83(3H, t, J 7.5 Hz); Anal. Calcd for C₁₇H₁₇N₇O.0.1 C₄H₈O₂: C, 60.72; H, 5.21, N, 28.49. Found: C, 60.85; H, 5.22; N, 28.29. 217 B 16 mp 146.7–149.3° C.; IR ν_(max)(DR)/cm⁻¹ 3518, 3323, 2955, 1605, 1511; NMR δ_(H) (400 MHz, DMSO) 8.14–8.13(1H, m), 7.92(1H, d, J 3.5 Hz), 7.79(1H, t, J 7.5 Hz), 7.35(2H, br s), 7.35(1H, d, J 7.5 Hz), 7.05(1H, d, J 7.5 Hz), 6.87(1H, dd, J 1.5, 3.5 Hz), 5.75(2H, s), 4.46(2H, s), 3.22(2H, d, J 6.5 Hz), 1.77–1.87(1H, m), 0.85(6H, d, J 6.5 Hz); Anal. Calcd for C₁₉H₂₁N₇O₂.0.5 H₂O: C, 58.75; H, 5.71, N, 25.24. Found: C, 58.87; H, 5.49; N, 24.92. 218 B 14 mp 196.0–196.1° C.; IR ν_(max)(DR)/cm⁻¹ 3481, 3325, 3203, 1646, 1607, 1518, 1488; NMR δ_(H)(400 MHz, DMSO) 8.14(1H, m), 7.92(1H, d, J 3.5 Hz), 7.80 (1H, t, J 7.5 Hz), 7.50(1H, d, J 7.5 Hz), 7.38(2H, br s), 7.04(1H, d, J 7.5 Hz), 6.87(1H, dd, J 1.5, 3.5 Hz), 5.77(2H, s), 4.64(2H, s). 219 C 37 IR ν_(max)(DR)/cm⁻¹ 3480, 3379, 3199, 2958, 2761, 2104, 1879, 1776, 1659, 1516, 1439, 1334, 1024, 762 and 575; NMR δ_(H)(400 MHz, DMSO) 1.10(6H, d, J 7.0 Hz), 2.92(1H, sept, J 6.5 Hz), 4.93(2H, s), 5.44(2H, s), 6.54(1H, d, J 8.0 Hz), 6.80–6.88(2H, m), 7.09(1H, d, J 2.0 Hz), 7.34(2H, s), 7.88(1H, d, J 3.5 Hz), 8.10–8.13(1H, m). Anal. Calcd for C₁₈H₁₉N₇O.0.3 H₂O: C, 60.93; H, 5.57; N, 27.63. Found: C, 60.77; H, 5.50; N, 27.42. 220 AV 26 mp 223.3–223.4° C.; NMR δ_(H)(400 MHz, DMSO) 8.14(1H, m), 7.92(1H, dd, J 1.0, 3.5 Hz), 7.82(1H, t, J 7.5 Hz), 7.37(1H, d, J 7.5 Hz), 7.36(2H, br s), 7.07 (1H, d, J 7.5 Hz), 6.87(1H, dd, J 1.5, 3.5 Hz), 5.78(2H, s), 4.18(2H, s). 221 AW 7 NMR δ_(H)(400 MHz, DMSO) 9.48–9.45(1H, s), 8.12–8.10(1H, m), 7.90–7.88 (1H, dd, J 1.0, 3.5 Hz), 7.36–7.30(2H, s), 7.17–7.12(2H, dd, J 2.0, 8.5 Hz), 6.86–6.84(1H, dd, J 2.0, 3.5 Hz), 6.74–6.70(2H, dd, J 2.0, 8.5 Hz) and 5.53–5.51 (2H, s); M/Z 309(M+H)⁺. 222 B 18 IR ν_(max)(DR)/cm⁻¹ 3483, 3319, 3200, 2961, 1953, 1709, 1612, 1439, 1343, 1220, 995 and 761; NMR δ_(H)(400 MHz, DMSO) 6.37(2H, s), 6.86–6.91(1H, m), 7.35(2H, s), 7.94(1H, d, J 3.0 Hz), 8.15(1H, s), 8.37(2H, d, J 8.5 Hz), 8.43 (2H, d, J 8.5 Hz). Anal. Calcd for C₁₆H₁₁N₇O₄.0.2 H₂O: C, 52.09; H, 3.11; N, 26.58. Found: C, 51.94; H, 3.05; N, 26.27. 223 B 41 IR ν_(max)(DR)/cm⁻¹ 4013, 3601, 3456, 3209, 2959, 2237, 1938, 1708, 1625, 1505, 1171, 1002, 827 and 733; NMR δ_(H)(400 MHz, DMSO) 6.33(2H, s), 6.84–6.91 (1H, m), 7.34(2H, s), 7.94(1H, d, J 3.5 Hz), 8.09–8.18(3H, m), 8.28(2H, d, J 8.0 Hz). Anal. Calcd for C₁₇H₁₁N₇O₂.0.7 H₂O: C, 57.05; H, 3.49; N, 27.39. Found: C, 56.97; H, 3.12; N, 27.37. 224 AX 54 IR ν_(max)(DR)/cm⁻¹ 3423, 3321, 3212, 1641, 1511, 1420, 1316, 1136 and 780; NMR δ_(H)(400 MHz, DMSO) 0.87(3H, t, J 7.5 Hz), 1.54–1.66(2H, m), 2.96–3.04 (2H, m), 5.65(2H, s), 6.85–6.88(1H, m), 7.00–7.03(2H, m), 7.10–7.16 (1H, m), 7.30(1H, t, J 7.5 Hz), 7.36(2H, s), 7.91(1H, dd, J 3.5, 1.0 Hz), 8.12–8.15 (1H, m), 9.79(1H, s). Anal. Calcd for C₁₈H₁₉N₇O₃S: C, 52.29; H, 4.63; N, 23.70. Found: C, 52.22; H, 4.70; N, 23.36. 225 AX 47 IR ν_(max)(DR)/cm⁻¹ 3477, 3319, 3114, 1609, 1479, 1414, 1349, 1162, 956 and 763; NMR δ_(H)(400 MHz, DMSO) 5.63(2H, s), 5.85–6.89(1H, m), 6.92(1H, t, J 1.5 Hz), 7.02–7.11(3H, m), 7.26–7.33(2H, m), 7.37(2H, s), 7.93(1H, dd, J 3.5, 1.0 Hz), 8.12–8.15(1H, m), 10.62(1H, s). 226 AY 58 mp 221.4–221.5° C.; IR ν_(max)(DR)/cm⁻¹ 3569, 3134, 2701, 2421, 1656, 1460; NMR δ_(H)(400 MHz, DMSO) 8.14(1H, m), 7.92(1H, dd, J 1.0, 3.5 Hz), 7.88 (1H, t, J 7.5 Hz), 7.48(1H, d, J 7.5 Hz), 7.16(1H, d, J 7.5 Hz), 6.88–6.87(1H, m), 5.80(2H, s), 4.27–4.24(2H, m), 2.60–2.56(3H, m). 227 B 24 IR ν_(max)(DR)/cm⁻¹ 4011, 3491, 3377, 3210, 3125, 2975, 2663, 2106, 1924, 1740, 1618, 1438, 1201, 1004, 796 and 752: NMR δ_(H)(400 MHz, DMSO) 1.14(6H, t, J 6.5 Hz), 3.46(4H, q, J 6.5 Hz), 6.00(2H, s), 6.76(2H, d, J 9.0 Hz), 6.87(1H, s), 7.26(2H, s), 7.85–7.97(3H, m), 8.13(1H, s), Anal. Calcd for C₂₀H₂₁N₇O₂.0.6 H₂O: C, 59.72; H, 5.56; N, 24.38, Found: C, 60.00; H, 5.40; N, 24.03. 228 B 26 mp 164.3–169.3° C.; IR ν_(max)(DR)/cm⁻¹ 3376, 3199, 2964, 1659, 1613, 1516, 1441; NMR δ_(H)(400 MHz, DMSO) 8.53(1H, d, J 2.0 Hz), 8.12–8.11(1H, m), 7.89(1H, d, J 3.5 Hz), 7.62(1H, dd, J 2.5, 8.0 Hz), 7.35(2H, br s), 7.26(1H, d, J 7.5 Hz), 6.85(1H, dd, J 1.5, 3.5 Hz), 5.67(2H, s), 2.99(1H, sept, J 7.0 Hz), 1.20 (6H, d, J 7.0 Hz); Anal. Calcd for C₁₇H₁₇N₇O.0.5 H₂O: C, 59.29; H, 5.27, N, 28.47. Found: C, 59.28; H, 5.16; N, 28.23. 229 B 40 mp 258.2–258.4° C.; IR ν_(max)(DR)/cm⁻¹ 3367, 3200, 2932, 1671, 1243, 1178, 1033, 797 and 610; NMR δ_(H)(400 MHz, DMSO) 8.12–8.07(3H, m), 7.91(1H, d, J 3.5 Hz), 7.15–7.09(4H, m), 6.85(1H, dd, J 3.5, 1.5 Hz), 6.10(2H, s) and 3.89(3H, s). 230 B 25 IR ν_(max)(DR)/cm⁻¹ 3436, 3320, 3208, 2977, 1609, 1370, 1323, 1155, 1025, 840 and 768; NMR δ_(H)(400 MHz, DMSO) 8.12–8.10(1H, m), 7.89(1H, d, J 3.5 Hz), 7.78(1H, d, J 4.0 Hz), 7.73(1H, d, J 2.5 Hz), 7.33(2H, br s), 6.88–6.84 (2H, m), 6.76(1H, d, J 4.0 Hz), 6.07(2H, s) and 1.50(9H, s). 231 AF 76 mp 321.8–322.2° C.; IR ν_(max)(DR)/cm⁻¹ 3993, 3233, 1645, 1515, 1437, 1336, 1102, 854 and 759; NMR δ_(H)(400 MHz, DMSO) 11.56(1H, br s), 8.13–8.11 (1H, m), 7.91(1H, d, J 3.5 Hz), 7.58(1H, d, J 2.0 Hz), 7.55(1H, t, J 3.5 Hz), 7.42(2H, br s), 6.86(1H, dd, J 3.5, 2.0 Hz), 6.73(1H, d, J 2.0 Hz), 6.52(1H, dd, J 3.0, 2.0 Hz) and 5.94(2H, s). 232 AX 20 IR ν_(max)(DR)/cm⁻¹ 3216, 1713, 1610, 1505, 1421, 1185, 1124, 1026, 886 and 763; NMR δ_(H)(400 MHz, DMSO) 2.13(3H, s), 2.35(3H, s), 5.62(2H, s), 6.85–6.88 (1H, m), 6.90–6.94(1H, m), 6.98–7.03(1H, m), 7.11(1H, d, J 8.0 Hz), 7.30 (1H, t, J 7.5 Hz), 7.31(2H, s), 7.91(1H, d, J 3.5 Hz), 8.11–8.14(1H, m), 10.46 (1H, s). 233 AV 40 mp 219.7–222.3° C.; IR ν_(max)(DR)/cm⁻¹ 3326, 3191, 2821, 2772, 1595, 1504, 1432; NMR δ_(H)(400 MHz, DMSO) 8.13–8.12(1H, m), 7.91(1H, dd, J 1.0, 3.5 Hz), 7.74(1H, t, J 7.5 Hz), 7.35(1H, d, J 7.5 Hz), 7.31(2H, br s), 6.98(1H, d, J 7.5 Hz), 6.86(1H, dd, J 2.0, 3.5 Hz), 5.74(2H, s), 3.46(2H, s), 2.15(6H, s); Anal. Calcd for C₁₇H₁₈N₈O: C, 58.28; H, 5.18, N, 31.97. Found: C, 57.94; H, 5.17; N, 31.70. 234 AV 55 mp 168.3–168.5° C.; IR ν_(max)(DR)/cm⁻¹ 3416, 3322, 3180, 2911, 1646, 1612, 1509, 1436; NMR δ_(H)(400 MHz, DMSO) 8.13–8.12(1H, m), 7.91(1H, dd, J 1.0, 3.5 Hz), 7.74(1H, t, J 7.5 Hz), 7.32(1H, d, J 7.5 Hz), 7.31(2H, br s), 7.02(1H, d, J 7.5 Hz), 6.87–6.86(1H, m), 5.75(2H, s), 3.69(2H, s), 1.92(3H, s); Anal. Calcd for C₁₆H₁₅N₇OS.0.2 H₂O: C, 53.83; H, 4.35, N, 27.46. Found: C, 53.74; H, 4.29; N, 27.13. 235 B 3 mp 231.6–231.7° C.; IR ν_(max)(DR)/cm⁻¹ 3642, 3320, 3198, 1727, 1533, 1437, 1223, 1029, 842 and 639; NMR δ_(H)(400 MHz, DMSO) 8.18(1H, d, J 7.5 Hz), 8.13(1H, s), 8.00–7.93(2H, m), 7.91(1H, d, J 3.5 Hz), 7.89–7.82(1H, m), 7.34(2H, br s), 6.87(1H, dd, J 3.5, 1.5 Hz) and 6.01(2H, s). 236 AX 32 NMR δ_(H)(400 MHz, DMSO) 2.19(3H, s), 3.50(3H, s), 5.58(2H, s), 6.84–6.97 (3H, m), 7.08(1H, d, J 8.0 Hz), 7.20(1H, t, J 7.5 Hz), 7.35(2H, s), 7.58(1H, s), 7.91(1H, d, J 3.0 Hz), 8.13(1H, s) and 10.14(1H, s); retention time 0.97 min. 237 AV 40 mp 259.3–259.4° C.; IR ν_(max)(DR)/cm⁻¹ 3323, 3202, 1607, 1511; NMR δ_(H)(400 MHz, DMSO) 8.12–8.11(2H, m), 7.91(2H, dd, J 1.0, 3.5 Hz), 7.70–7.66(2H, m), 7.30(4H, br s), 7.10(4H, d, J 8.0 Hz), 6.85(2H, dd, J 1.5, 3.5 Hz), 5.73(4H, s), 4.23(4H, s), 2.78(3H, s). 238 AV 17 mp 238.2–238.6° C.; IR ν_(max)(DR)/cm⁻¹ 3189, 2908, 1653, 1592, 1470; NMR δ_(H) (400 MHz, DMSO) 8.13–8.12(1H, m), 7.91(1H, d, J 3.0 Hz), 7.85(1H, t, J 7.5 Hz), 7.43(1H, d, J 7.5 Hz), 7.30(2H, br s), 7.23(1H, d, J 7.5 Hz), 6.87–6.85 (1H, m), 5.81(2H, s), 4.56(2H, s), 2.87(3H, s). 239 AV 71 mp 205.8–206.0° C.; IR ν_(max)(Nujol)/cm⁻¹ 3502, 3304, 3185, 2923, 1628, 1510; NMR δ_(H)(400 MHz, DMSO) 8.13–8.12(1H, m), 7.92(1H, d, J 3.0 Hz), 7.83 (1H, t, J 8.0 Hz), 7.33(1H, d, J 8.0 Hz), 7.30(2H, br s), 7.17(1H, d, J 8.0 Hz), 6.87–6.86(1H, m), 5.79(2H, s), 4.31(2H, s), 2.84(3H, s), 2.67(3H, s); Anal. Calcd for C₁₇H₁₈N₈O₃S: C, 49.27; H, 4.38, N, 27.02. Found: C, 49.14; H, 4.49; N, 26.74. 240 C 24 mp 254.3–254.5.° C.; IR ν_(max)(DR)/cm⁻¹ 3443, 3342, 3187, 1647, 1593, 1513, 1414, 1300, 1268 and 1225; NMR δ_(H)(400 MHz, DMSO) 7.37(2H, s), 6.96(1H, t, J 7.8 Hz), 6.46(1H, dd, J 1.0, J 8.0 Hz), 6.40(2H, d, J 7.5 Hz), 6.33(1H, s), 5.56(2H, s), 5.2(2H, s), 2.5(3H, s) and 2.44(3H, s). 241 C 17 NMR δ_(H)(400 MHz, DMSO) 8.11–8.09(1H, m), 7.89–7.86(1H, dd, J 1.0, 3.5 Hz), 7.32–7.27(2H, s), 7.22–6.95(1H, t, J 9.0 Hz), 6.85–6.83(1H, dd, J 2.0, 3.5 Hz), 6.35–6.29(2H, m), 5.48–5.46(2H, s) and 5.46–5.44(2H, s); Retention time 1.18 min. 242 B 15 IR ν_(max)(DR)/cm⁻¹ 3850, 3667, 2923, 1730, 1601, 1464, 1023, 751 and 593; NMR δ_(H)(400 MHz, DMSO) 3.68(1H, dd, J 16.0, 5.5 Hz), 3.88(1H, dd, J 16.0, 9.0 Hz), 6.05(1H, dd, J 8.5, 5.5 Hz), 6.84–6.89(1H, m), 7.29(2H, s), 7.57(1H, t, J 7.0 Hz), 7.72(1H, d, J 7.5 Hz), 7.78–7.87(2H, m), 7.91(1H, d, J 3.5 Hz), 8.13 (1H, s). Anal. Calcd for C₁₇H₁₂N₆O₂.0.2 H₂O: C, 60.87; H, 3.72; N, 25.02. Found: C, 60.89; H, 3.68; N, 24.85. 243 AF 53 mp > 300° C. dec; IR ν_(max)(DR)/cm⁻¹ 3212, 2923, 1642, 1605, 1510, 1461, 1377, 1023 and 757; NMR δ_(H)(400 MHz, DMSO) 11.16(1H, br s), 8.12(1H, s), 7.91 (1H, d, J 3.5 Hz), 7.44–7.36(3H, m), 7.29(1H, s), 6.86(1H, dd, J 3.5, 1.5 Hz), 6.58(1H, s), 6.42–6.38(1H, m), 5.87(2H, s) and 2.27(3H, s). 244 BB 7 IR ν_(max)(Nujol)/cm⁻¹ 3319, 2924, 1646, 1606, 1462; NMR δ_(H)(400 MHz, DMSO) 9.54(1H, s), 8.27–8.26(1H, m), 8.12–8.11(1H, m), 7.90(1H, d, J 3.5 Hz), 7.71(1H, d, J 8.0 Hz), 7.32(2H, br s), 7.17–7.15(1H, m), 7.11–7.09(1H, m), 6.86–6.85(1H, m), 5.59(2H, s), 2.18(3H, s). 245 B 22 IR ν_(max)(Nujol)/cm⁻¹ 3849, 3500, 3298, 3174, 2924, 1698, 1631, 1604, 1456, 1379, 1226, 1027, 953 and 753; NMR δ_(H)(400 MHz, DMSO) 1.91(3H, d, J 7.0 Hz), 6.63(1H, q, J 7.0 Hz), 6.84–6.87(1H, m), 7.32(2H, s), 7.54(2H, t, J 8.0 Hz), 7.66(1H, tt, J 7.5, 2.0 Hz), 7.88(1H, d, J 3.5 Hz), 7.98–8.03(2H, m), 8.11–8.12 (1H, m). Anal. Calcd for C₁₇H₁₄N₆O₂: C, 61.07; H, 4.22; N, 25.12. Found: C, 60.72; H, 4.27; N, 24.75. 246 BE 81 IR ν_(max)(Nujol;)/cm⁻¹ 3313, 3189, 2924, 1605, 1461, 1377, 1236, 1026 and 762; NMR δ_(H)(400 MHz, DMSO) 11.62(1H, br s), 8.11(1H, dd, J 2.0, 1.0 Hz), 7.90 (1H, d, J 3.5 Hz), 7.41(1H, t, J 2.5 Hz), 7.37–7.29(3H, m), 6.94(1H, d, J 11.0 Hz), 6.85(1H, dd, J 3.5, 2.0 Hz) 6.52–6.47(1H, m) and 5.71(2H, s). 247 B 28 mp 134.5–134.6° C.; IR ν_(max)(Nujol)/cm⁻¹ 3306, 3189, 2924, 1635, 1610, 1580; NMR δ_(H)(400 MHz, DMSO) 8.13–8.12(1H, m), 7.92–7.91(1H, m), 7.79–7.75 (1H, m), 7.35(1H, d, J 8.0 Hz), 7.31(2H, br s), 7.03(1H, d, J 7.5 Hz), 6.86(1H, dd, J 3.5, 1.5 Hz), 5.74(2H, s), 4.46(2H, s), 3.65(1H, sept, J 6.0 Hz), 1.12(6H, d, J 6.0 Hz); Anal. Calcd for C₁₈H₁₉N₇O₂.1.2 H₂O: C, 55.86; H, 5.57, N, 25.33. Found: C, 55.80; H, 5.41; N, 25.05. 248 B 11 mp 158.9.–161.3° C.; IR ν_(max)(Nujol)/cm⁻¹ 3301, 3185, 2923, 1636, 1611, 1570, 1536, 1501, 1324 and 1210; NMR δ_(H)(400 MHz, DMSO) 7.88(1H, d, J 3.0 Hz), 7.66(1H, t, J 7.5 Hz), 7.27(2H, br s) 7.18(1H, d, J 7.5 Hz), 6.89(1H, d, J 7.5 Hz), 6.51(1H, dd, J 1.0, J 3.5 Hz), 5.71(2H, s), 2.69(2H, q, J 7.5 Hz), 2.46 (3H, s) and 1.15(3H, J 7.5 Hz). 249 BE 76 IR ν_(max)(DR;)/cm⁻¹ 3319, 2928, 1605, 1334, 1226, 1027, 737 and 528; NMR δ_(H) (400 MHz, DMSO) 11.47(1H, s), 8.14–8.09(1H, m) 7.89(1H, d, J 3.5 Hz), 7.48(1H, d, J 3.0 Hz), 7.38–7.27(3H, m), 6.94(1H, d, J 13.0 Hz), 6.85(1H, dd, J 3.5, 2.0 Hz), 6.52–6.47(1H, m) and 5.81(2H, s). 250 BE 68 IR ν_(max)(DR)/cm⁻¹ 3318, 2923, 1640, 1579, 1455, 1377, 1079, 1022, 750 and 588; NMR δ_(H)(400 MHz, DMSO) 11.13(1H, br s), 8.23(1H, s), 8.05–8.04(1H, m), 7.43(1H, d, J 3.5 Hz), 7.30(2H, s), 7.00(1H, t, J 7.0 Hz), 6.90(2H, s), 6.80–6.77 (1H, m), 6.73(1H, d, J 6.5 Hz), 6.51(1H, s) and 5.63(2H, s). 251 BE 42 mp 294.0–294.2° C.; IR ν_(max)(DR)/cm⁻¹ 3498, 3414, 1612, 1318, 1235, 102, 765 and 589; NMR δ_(H)(400 MHz, DMSO) 11.24(1H, br s), 8.12(1H, s), 7.91(1H, d, J 3.5 Hz), 7.53(1H, s), 7.39(1H, t, J 2.5 Hz) 7.36–7.26(3H, m), 6.88–6.82 (1H, m), 6.43–6.38(1H, m) and 5.76(2H, s) 252 BF 44 mp 200.2–201.2° C. IR ν_(max)(DR)/cm⁻¹ 3390, 3205, 2924, 1725, 1648, 1603, 1508, 1423, 1332, 1277 and 1158; NMR δ_(H)(400 MHz, DMSO) 8.12(1H, s), 7.90(1H, d, J 3.5 Hz), 7.35–7.25(4H, m), 7.07–6.97(3H, m), 6.86(1H, dd, J 1.5, J 3.5 Hz), 6.45(2H, t, J 7.5 Hz), 6.37(1H, s), 6.32(1H, t, J 6.0 Hz), 5.49(2H, s) and 4.16(2H, s, J 6.0 Hz). 253 B 18 mp 181.8–182.1° C.; IR ν_(max)(DR)/cm⁻¹ 3362, 3208, 2988, 1654, 1601, 1513; NMR δ_(H)(400 MHz, DMSO) 8.13–8.12(1H, m), 7.91(1H, d, J 3.5 Hz), 7.68 (1H, m), 7.29(2H, br s), 6.87–6.85(1H, m), 6.74(1H, d, J 7.5 Hz), 6.68(1H, d, J 8.0 Hz), 5.69(2H, s), 4.07(2H, q, J 7.0 Hz), 1.12(3H, t, J 7.0 Hz). 254 B 14 mp 190.8–190.9° C.; IR ν_(max)(DR)/cm⁻¹ 3514, 3292, 3158, 2984, 1615, 1500; NMR δ_(H)(400 MHz, DMSO) 7.88(1H, d, J 3.5 Hz), 7.65(1H, dd, J 7.0, 8.0 Hz), 7.25(2H, br s), 6.72(1H, d, J 7.0 Hz), 6.68(1H, d, J 8.0 Hz), 6.52–6.50(1H, m), 5.67(2H, s), 4.08(2H, q, J 7.0 Hz), 2.46(3H, s), 1.12(3H, t, J 7.0 Hz). 255 BF 20 mp 184.5–184.6° C.; IR ν_(max)(DR)/cm⁻¹ 3202, 1649, 1601, 1509, 1436, 1331, 1277 and 1221; NMR δ_(H)(400 MHz, DMSO) 8.43(1H, d, J 4.89 Hz), 8.12(1H, dd, J 0.8, 3.5 Hz), 7.91(1H, dd, J 0.9, 3.5 Hz), 7.65(1H, td, J 1.7, 7.7 Hz), 7.30 (2H, br s), 7.25(1H, d, J 7.9 Hz), 7.15(1H, dd, J 4.9, 7.5 Hz), 7.0(1H, t, J 7.8 Hz), 6.86(1H, dd, J 1.7, 3.5 Hz), 6.48–6.36(4H, m), 5.49(2H, s), 4.27(2H, s); Anal. Calcd for C₂₁H₁₈N₈O.0.3 H₂O: C, 62.46; H, 4.64, N, 27.75. Found: C, 62.66; H, 4.57; N, 27.36. 256 B 6 Mp 167.6–168.1° C. IR ν_(max)(DR)/cm⁻¹ 3509, 3304, 3178, 1609, 1494, 1421, 1325, 1127, 839 and 752. NMR δ_(H)(400 MHz, DMSO) 2.05(3H, d, J 7.0 Hz), 6.14(1H, q, J 7.0 Hz), 6.84–6.88(1H, m), 7.30(2H, s), 7.52(2H, d, J 8.5 Hz), 7.73(2H, d, J 8.0 Hz), 7.91(1H, dd, J 3.5, 1.0 Hz), 8.11–8.13(1H, m). Anal. Calcd for C₁₇H₁₃N₆F₃O: C, 54.55; H, 3.50; N, 22.44. Found: C, 54.52; H, 3.65; N, 22.06. 257 BE 75 IR ν_(max)(DR)/cm⁻¹ 3459, 3348, 3187, 2960, 1648, 1513, 1351, 1244, 1011, 837 and 759; NMR δ_(H)(400 MHz, DMSO) 11.18(1H, br s), 8.11(1H, s), 7.89(1H, d, J 3.0 Hz), 7.42(1H, d, J 7.5 Hz), 7.37–7.26(3H, m), 7.21(1H, d, J 11.0 Hz), 6.89–6.81(1H, m), 6.43–6.37(1H, s) and 5.72(2H, s). 258 BE 94 mp > 300° C.; dec; IR ν_(max)(DR)/cm⁻¹ 3441, 3318, 2990, 1612, 1285, 1083, 839 and 593; NMR δ_(H)(400 MHz, DMSO) 11.29(1H, br s), 8.12(1H, s), 7.91(1H, d, J 3.5 Hz), 7.41–7.29(3H, m), 7.22(1H, dd, J 10.0, 2.5 Hz), 6.90(1H, dd, J 9.5, 2.5 Hz), 6.86(1H, dd, J 3.5, 1.5 Hz), 6.30(1H, s) and 5.79(2H, s). 259 B 50 mp 228.4–228.5° C.; NMR δ_(H)(400 MHz, DMSO) 8.13–8.12(1H, m), 7.91 (1H, d, J 3.5 Hz), 7.34(2H, br s), 7.18(2H, s), 6.87–6.85(1H, m), 5.67(2H, s), 2.22(6H, s). 260 B 8 mp 150.3–151.0° C. IR ν_(max)(DR)/cm⁻¹ 3510, 3306, 3183, 1633, 1495, 1423, 1240, 1029 and 753; NMR δ_(H)(400 MHz, DMSO) 2.02(3H, d, J 7.0 Hz), 6.05 (1H, q, J 7.0 Hz), 6.83–6.88(1H, m), 7.10–7.22(3H, m), 7.30(2H, s), 7.40 (1H, dt, J 8.0, 6.5 Hz), 7.91(1H, dd, J 3.5, 1.0 Hz), 8.10–8.13(1H, m). Anal. Calcd for C₁₆H₁₃N₆OF.0.25 H₂O: C, 58.44; H, 4.14; N, 25.56. Found: C, 58.48; H, 3.98; N, 25.40. 261 BE 91 IR ν_(max)(DR)/cm⁻¹ 3472, 3318, 3184, 2922, 1651, 1595, 1478, 1417, 1329, 1218, 1097, 1015, 870, 767 and 545; NMR δ_(H)(400 MHz, DMSO) 11.50(1H, s), 8.11 (1H, s), 7.90(1H, d, J 3.5 Hz), 7.47(1H, s), 7.42(1H, t, J 3.0 Hz), 7.33(2H, s), 7.19(1H, s), 6.86–6.84(1H, m), 6.53–6.51(1H, m), 5.71(2H, s). 262 C 34 mp 250.1–261.3° C.; IR ν_(max)(DR)/cm⁻¹ 3325, 3205, 2968, 1603, 1488; NMR δ_(H) (400 MHz, DMSO) 8.11–8.10(1H, m), 7.89–7.87(1H, m), 7.28(2H, br s), 6.85–6.83 (1H, m), 6.81(2H, s), 5.40(2H, s), 4.56(2H, br s), 2.03(6H, s). 263 K 72 IR ν_(max)(DR)/cm⁻¹ 2825, 2021, 1645, 1453, 1394, 1286, 1171, 1030, 779 and 619; NMR δ_(H)(400 MHz, DMSO) 2.02(3H, d, J 7.0 Hz), 6.07(1H, q, J 7.0 Hz), 6.85–6.88(1H, m), 7.13–7.18(1H, m), 7.25(1H, d, J 8.5 Hz), 7.36(1H, d, J 8.0 Hz), 7.47(1H, t, J 7.5 Hz), 7.92(1H, d, J 3.5 Hz), 8.12–8.14(1H, m). Anal. Calcd for C₁₆H₁₅N₇O.2HCl.0.8 H₂O: C, 47.02; H, 4.59; N, 23.99. Found: C, 46.87; H, 4.43; N, 23.71. 264 B 26 mp 162.0–162.6° C.; IR ν_(max)(DR)/cm⁻¹ 3319, 3206, 2932, 1644, 1505; NMR δ_(H) (400 MHz, DMSO) 8.13–8.12(1H, m), 7.92–7.91(1H, m), 7.68–7.64(1H, m), 7.31(2H, br s), 7.21(1H, d, J 7.5 Hz), 6.92(1H, d, J 8.0 Hz), 6.86(1H, dd, J 3.5, 1.5 Hz), 5.74(2H, s), 3.58(2H, t, J 6.5 Hz), 3.16(3H, s), 2.84(2H, t, J 6.5 Hz); M/Z 352(M+H)⁺. 265 B 15 NMR δ_(H)(400 MHz, DMSO) 8.12–8.11(1H, m), 7.92–7.90(1H, m), 7.47(1H, d, J 8.0 Hz), 7.28(2H, br s), 6.91(1H, d, J 8.0 Hz), 6.86(1H, dd, J 2.0, 3.5 Hz), 5.73–5.69(1H, m), 2.60–2.46(2H, m), 2.39(3H, s), 2.20(3H, s), 0.87(3H, t, J 7.0 Hz); M/Z 350(M+H)⁺. 266 AK 99 NMR δ_(H)(400 MHz, DMSO) 8.22–8.17(2H, m), 7.94(1H, d, J 2.01 Hz), 7.73–7.63 (2H, m), 7.37(1H, d, J 2.5 Hz) and 5.86(2H, s); M/Z 338(M+H)⁺; Retention time 1.74 min. 267 B 58 mp 255.6–255.7° C.; IR ν_(max)(DR)/cm⁻¹ 3512, 3294, 3179, 2960, 2692, 1745, 1638, 1432 and 1371; NMR δ_(H)(400 MHz, DMSO) 7.88(1H, d, J 3.51 Hz), 7.81 (1H, dd, J 1.0, J 8.0 Hz), 7.46–7.29(2H, br s), 7.40(1H, t, J 7.8 Hz), 7.23(1H, d, J 8.0 Hz), 6.51(1H, dd, J 1.0, 3.5 Hz), 5.78(2H, s) and 2.46(6H, s). 268 B 40 mp 248.1–249.0° C. IR ν_(max)(DR)/cm⁻¹ 3507, 3308, 3190, 2952, 1626, 1571, 1519, 1434, 1348 and 1291; NMR δ_(H)(400 MHz, DMSO) 8.22(2H, d, J 8.5 Hz), 7.89(1H, d, J 3.5 Hz), 7.49(2H, d, J 9.0 Hz), 7.36(2H, br s), 6.52(1H, dd, J 1.0, 3.5 Hz), 5.83(2H, s) and 2.46(3H, s). 269 B 18 NMR δ_(H)(400 MHz, DMSO) 8.14–8.12(1H, m), 7.92–7.90(1H, dd, J 1.0, 3.5 Hz), 7.42–7.34(2H, s), 7.26–7.25(4H, s), 6.87–6.85(1H, dd, J 1.5, 3.5 Hz), 5.66–5.64(2H, s), 3.15–3.13(3H, s) and 1.38–1.36(9H, s). 270 H 46 NMR δ_(H)(400 MHz, DMSO) 8.22–8.13(2H, m), 7.75–7.65(3H, m), 7.59(1H, dd, J 1.5, J 3.0 Hz), 7.34(2H, br s), 6.96(1H, dd, J 1.5, J 3.5 Hz), 6.45(1H, t, J 3.2 Hz), 5.85(2H, s) and 1.22(9H, s); M/Z 437(M+H)⁺; Retention time 4.36 min. 271 Q 40 NMR δ_(H)(400 MHz, DMSO) 8.21–8.17(2H, m), 7.71–7.63(2H, m), 7.48(2H, br s), 5.87(2H, s), 2.50(3H, s) and 2.44(3H, s); M/Z 383(M+H)⁺; Retention time 3.69 min. 272 B NMR δ_(H)(400 MHz, DMSO) 8.18(1H, dd, J 9.6, 2.0 Hz), 8.13(1H, d, J 1.6 Hz), 8.05(1H, dd, J 8.4, 2.4 Hz), 7.90(1H, d, J 3.2 Hz), 7.45(1H, t, J 8.0 Hz), 7.38 (2H, br s), 6.86(1H, dd, J 3.6, 2.0 Hz) and 5.84(2H, s). 273 B NMR δ_(H)(400 MHz, DMSO) 8.13–8.09(1H, m), 7.89(1H, d, J 3.5 Hz), 7.66 (1H, d, J 3.5 Hz), 7.39(1H, s), 7.29(2H, br s), 6.85(1H, dd, J 3.5, 2.0 Hz), 6.68 (1H, d, J 3.5 Hz), 6.65(1H, s), 2.27(3H, s) and 1.52(9H, s). 274 BA 99 IR ν_(max)(Nujol)/cm⁻¹ 3313, 2923, 1693, 1603; NMR δ_(H)(400 MHz, DMSO) 8.78 (1H, br s), 8.12–8.11(1H, m), 7.90(1H, d, J 3.5 Hz), 7.34–7.31(3H, m), 7.13–7.12 (1H, m), 7.08–7.05(1H, m), 6.86–6.85(1H, m), 5.58(2H, s), 4.08(2H, q, J 7.0 Hz), 2.16(3H, s), 1.21(3H, t, J 7.0 Hz). Adenosine Receptor Binding Binding Affinities at hA_(2A) Receptors

The compounds were examined in an assay measuring in vitro binding to human adenosine A_(2A) receptors by determining the displacement of the adenosine A_(2A) receptor selective radioligand [³H]-CGS 21680 using standard techniques. The results are summarised in Table 3.

TABLE 3 Example K_(i) (nM) Example 3 3 Example 4 4 Example 5 3 Example 8 3 Example 11 2 Example 12 7 Example 13 2 Example 15 4 Example 41 2 Example 57 2 Example 78 3 Example 92 2 Example 107 2 Example 120 1 Example 149 1 Example 156 2 Example 169 2 Example 188 1 Example 202 1 Example 209 1 Example 221 2 Example 233 4 Example 255 4 Evaluation of Potential Anti-Parkinsonian Activity in vivo Haloperidol-induced Hypolocomotion Model

It has previously been demonstrated that adenosine antagonists, such as theophylline, can reverse the behavioural depressant effects of dopamine antagonists, such as haloperidol, in rodents (Mandhane S. N. et al., Adenosine A₂ receptors modulate haloperidol-induced catalepsy in rats. Eur. J. Pharmacol. 1997, 328, 135–141). This approach is also considered a valid method for screening drugs with potential antiparkinsonian effects. Thus, the ability of novel adenosine antagonists to block haloperidol-induced deficits in locomotor activity in mice can be used to assess both in vivo and potential antiparkinsonian efficacy.

Method

Female TO mice (25–30 g) obtained from TUCK, UK, are used for all experiments. Animals are housed in groups of 8 [cage size −40 (width)×40 (length)×20 (height)cm] under 12 hr light/dark cycle (lights on 08:00 hr), in a temperature (20±2° C.) and humidity (55±15%) controlled environment. Animals have free access to food and water, and are allowed at least 7 days to acclimatize after delivery before experimental use.

Drugs

Liquid injectable haloperidol (1 ml Serenance ampoules from Baker Norton, Harlow, Essex, each containing haloperidol BP 5 mg, batch # P424) are diluted to a final concentration of 0.02 mg/ml using saline. Test compounds are typically prepared as aqueous suspensions in 8% Tween. All compounds are administered intraperitoneally in a volume of 10 ml/kg.

Procedure

1.5 hours before testing, mice are administered 0.2 mg/kg haloperidol, a dose that reduces baseline locomotor activity by at least 50%. Test substances are typically administered 5–60 minutes prior to testing. The animals are then placed individually into clean, clear polycarbonate cages [20 (width)×40 (length)×20 (height) cm, with a flat perforated, Perspex lid]. Horizontal locomotor activity is determined by placing the cages within a frame containing a 3×6 array of photocells linked to a computer, which tabulates beam breaks. Mice are left undisturbed to explore for 1 hour, and the number of beams breaks made during this period serves as a record of locomotor activity which is compared with data for control animals for statistically significant differences.

6-OHDA Model

Parkinson's disease is a progressive neurodegenerative disorder characterised by symptoms of muscle rigidity, tremor, paucity of movement (hypokinesia), and postural instability. It has been established for some time that the primary deficit in PD is a loss of dopaminergic neurones in the substantia nigra which project to the striatum, and indeed a substantial proportion of striatal dopamine is lost (ca 80–85%) before symptoms are observed. The loss of striatal dopamine results in abnormal activity of the basal ganglia, a series of nuclei which regulate smooth and well co-ordinated movement (Blandini F. et al., Glutamate and Parkinson's Disease. Mol. Neurobiol. 1996, 12, 73–94). The neurochemical deficits seen in Parkinson's disease can be reproduced by local injection of the dopaminergic neurotoxin 6-hydroxydopamine into brain regions containing either the cell bodies or axonal fibres of the nigrostriatal neurones.

By unilaterally lesioning the nigrostriatal pathway on only one-side of the brain, a behavioural asymmetry in movement inhibition is observed. Although unilaterally-lesioned animals are still mobile and capable of self maintenance, the remaining dopamine-sensitive neurones on the lesioned side become supersenstive to stimulation. This is demonstrated by the observation that following systemic administration of dopamine agonists, such as apomorphine, animals show a pronounced rotation in a direction contralateral to the side of lesioning. The ability of compounds to induce contralateral rotations in 6-OHDA lesioned rats has proven to be a sensitive model to predict drug efficacy in the treatment of Parkinson's Disease.

Animals

Male Sprague-Dawley rats, obtained from Charles River, are used for all experiments. Animals are housed in groups of 5 under 12 hr light/dark cycle (lights on 08:00 hr), in a temperature (20±2° C.) and humidity (55±15%) controlled environment. Animals have free access to food and water, and are allowed at least 7 days to acclimatize after delivery before experimental use.

Drugs

Ascorbic acid, desipramine, 6-OHDA and apomorphine (Sigma-Aldrich, Poole, UK). 6-OHDA is freshly prepared as a solution in 0.2% ascorbate at a concentration of 4 mg/mL prior to surgery. Desipramine is dissolved in warm saline, and administered in a volume of 1 ml/kg. Apomorphine is dissolved in 0.02% ascorbate and administered in a volume of 2 mL/kg. Test compounds are suspended in 8% Tween and injected in a volume of 2 mL/kg.

Surgery

15 minutes prior to surgery, animals are given an intraperitoneal injection of the noradrenergic uptake inhibitor desipramine (25 mg/kg) to prevent damage to non-dopamine neurones. Animals are then placed in an anaesthetic chamber and anaesthetised using a mixture of oxygen and isoflurane. Once unconscious, the animals are transferred to a stereotaxic frame, where anaesthesia is maintained through a mask. The top of the animal's head is shaved and sterilised using an iodine solution. Once dry, a 2 cm long incision is made along the midline of the scalp and the skin retracted and clipped back to expose the skull. A small hole is then drilled through the skill above the injection site. In order to lesion the nigrostriatal pathway, the injection cannula is slowly lowered to position above the right medial forebrain bundle at −3.2 mm anterior posterior, −1.5 mm medial lateral from bregma, and to a depth of 7.2 mm below the duramater. 2 minutes after lowing the cannula, 2 μL of 6-OHDA is infused at a rate of 0.5 μl/min over 4 minutes, yeilding a final dose of 8 μg. The cannula is then left in place for a further 5 minutes to facilitate diffusion before being slowly withdrawn. The skin is then sutured shut using Ethicon W501 Mersilk, and the animal removed from the strereotaxic frame and returned to its homecage. The rats are allowed 2 weeks to recover from surgery before behavioural testing.

Apparatus

Rotational behaviour is measured using an eight station rotameter system provided by Med Associates, San Diego, USA. Each station is comprised of a stainless steel bowl (45 cm diameter×15 cm high) enclosed in a transparent Plexiglas cover running around the edge of the bowl, and extending to a height of 29 cm. To assess rotation, rats are placed in cloth jacket attached to a spring tether connected to optical rotameter positioned above the bowl, which assesses movement to the left or right either as partial (45°) or full (360°) rotations. All eight stations are interfaced to a computer that tabulated data.

Procedure

To reduce stress during drug testing, rats are initially habituated to the apparatus for 15 minutes on four consecutive days. On the test day, rats are given an intraperitoneal injection of test compound 30 minutes prior to testing. Immediately prior to testing, animals are given a subcutaneous injection of a subthreshold dose of apomorphine, then placed in the harness and the number of rotations recorded for one hour. The total number of full contralatral rotations during the hour test period serves as an index of antiparkinsonian drug efficacy. 

1. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier:

wherein R₁ is selected from the group consisting of H, alkyl, aryl, alkoxy, aryloxy, alkylthio, arylthio, halogen, CN, NR₅R₆, NR₄COR₅, NR₄CONR₅R₆, NR₄CO₂R₇ and NR₄SO₂R₇; R₂ is an aryl attached via an unsaturated ring carbon of said aryl group; R₃ is selected from the group consisting of H, alkyl, COR₅, CO₂R₇, CONR₅R₆, CONR₄NR₅R₆ and SO₂R₇; R₄, R₅ and R₆ are independently selected from the group consisting of H, alkyl and aryl, or where R₅ and R₆ are in an NR₅R₆ group, R₅ and R₆ may be linked to form a heterocyclic group, or where R₄, R₅ and R₆ are in a (CONR₄NR₅R₆) group, R₄ and R₅ may be linked to form a heterocyclic group; and R₇ is selected from the group consisting of alkyl and aryl.
 2. The composition according to claim 1 wherein R₁ is selected from the group consisting of alkyl, aryl, alkoxy, aryloxy, alkylthio, arylthio, halogen, CN, NR₅R₆, NR₄COR₅, NR₄CONR₅R₆, NR₄CO₂R₇ and NR₄SO₂R₇.
 3. The composition according to claim 1 wherein R₁ is selected from the group consisting of alkyl, alkoxy, alkylthio, NR₅R₆, NR₄COR₅, NR₄CONR₅R₆, NR₄CO₂R₇ and NR₄SO₂R₇.
 4. The composition according to claim 1 wherein R₁ is selected from the group consisting of NR₅R₆, NR₄COR₅, NR₄CONR₅R₆, NR₄CO₂R₇ and NR₄SO₂R₇.
 5. The composition according to claim 1 wherein R₁ is NR₅R₆.
 6. The composition according to claim 1 wherein R₁ is NH₂.
 7. The composition according to claim 1 wherein R₁ is selected from the group consisting of haloalkyl and arylalkyl.
 8. The composition according to claim 1 wherein R₂ is not ortho, ortho-disubstituted.
 9. The composition according to claim 1 wherein R₂ is not substituted at either ortho position.
 10. The composition according to claim 1 wherein R₂ is a heteroaryl group.
 11. The composition according to claim 10 wherein R₂ is a heteroaryl group which is attached to the pyrimidine ring of formula (I) such that a heteroatom is adjacent to the unsaturated carbon atom attached to said pyrimidine ring.
 12. The composition according to claim 10 wherein R₂ is an N, O or S-containing heteroaryl group.
 13. The composition according to claim 10 wherein R₂ is selected from the group consisting of furyl, thienyl, pyridyl, thiazolyl, pyrazolyl, triazolyl, pyrrolyl and oxazolyl.
 14. The composition according to claim 10 wherein R₂ is selected from the group consisting of 2-furyl, 2-thienyl, 2-thiazolyl, 2-pyridyl, 3-pyrazolyl, 2-pyrrolyl, 4-triazolyl and 5-oxazolyl.
 15. The composition according to claim 10 wherein R₂ is selected from the group consisting of furyl, thienyl, pyridyl, thiazolyl and pyrazolyl.
 16. The composition according to claim 10 wherein R₂ is selected from the group consisting of 2-furyl, 2-thienyl, 2-thiazolyl, 2-pyridyl and 3-pyrazolyl.
 17. The composition according to claim 10 wherein R₂ is 2-furyl.
 18. The composition according to claim 1 wherein R₂ is phenyl.
 19. The composition according to claim 1 wherein R₃ is selected from the group consisting of H and substituted alkyl.
 20. The composition according to claim 19 wherein R₃ is an alkyl substituted by a substituent selected from the group consisting of aryl, cycloalkyl, non-aromatic heterocyclyl, CN, CO₂R₅, CONR₅R₆, CONR₄NR₅R₆ and C(═NR₄)NR₅R₆.
 21. The composition according to claim 19 wherein R₃ is an alkyl substituted by aryl.
 22. The composition according to claim 21 wherein R ₃ is (CR₉R₁₀)_(n)R₁₁ wherein n is 1 to 6, R₉ and R₁₀ are independently selected from H, alkyl and aryl, and R₁₁ is a substituted aryl or substituted heteroaryl.
 23. The composition according to claim 22 wherein R₁₁ is selected from the group consisting of mono-substituted, di-substituted, and tri-substituted aryl groups represented by the formula Ar(R₁₂)_(a)(R₁₃)_(b)(R₁₄)_(c) wherein: Ar is an aryl group; R₁₂, R₁₃ and R₁₄ are substituent group(s), the same or different; and a, b and c are 0 or 1 such that a+b+c≧1.
 24. The composition according to claim 22 wherein n is 1 to
 3. 25. The composition according to claim 22 wherein n is
 1. 26. The composition according to claim 22 wherein each of R₉ and R₁₀ are selected from H and alkyl.
 27. The composition according to claim 22 wherein at least one of R₉ and R₁₀ is H.
 28. The composition according to claim 22 wherein both R₉ and R₁₀ are H.
 29. The composition according to claim 23 wherein R₁₂, R₁₃ and R₁₄ are independently selected from the group consisting of NR₅R₆, alkyl, alkoxy, halogen, NO₂, CN, hydroxy, NHOH, CHO, CONR₅R₆, CO₂R₅, NR₄COR₅, NR₄CO₂R₇, NR₄SO₂R₇, OCO₂R₇, and aryl.
 30. The composition according to claim 23 wherein R₁₂, R₁₃ and R₁₄ are independently selected from the group consisting of NR₅R₆, alkyl and halogen.
 31. The composition according to claim 29 wherein R₁₂, R₁₃ and R₁₄ are a substituted alkyl which is selected from the group consisting of alkoxyalkyl, hydroxyalkyl, aminoalkyl and haloalkyl.
 32. The composition according to claim 29 wherein R₁₂, R₁₃ and R₁₄ are independently selected from the group consisting of unsubstituted alkyl, NH₂ and fluoro.
 33. The composition according to claim 22 wherein said substituted aryl group R₁₁ or Ar is selected from the group consisting of phenyl, pyridyl, indolyl, furyl, thienyl, isoindolyl, indolinyl, isoxazolyl, oxazolyl, thiazolyl, pyrazinyl, pyrimidinyl, quinolinyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, indazolyl, benzodioxolyl and dihydrobenzofuranyl.
 34. The composition according to claim 22 wherein said substituted aryl group R₁₁ or Ar is selected from the group consisting of phenyl, pyridyl, indolyl, furyl and thienyl.
 35. The composition according to claim 34 wherein said substituted aryl group R₁₁ or Ar is selected from the group consisting of phenyl, thienyl, furyl and pyridyl.
 36. The composition according to claim 34 wherein said substituted aryl group R₁₁ or Ar is selected from the group consisting of phenyl, 2-thienyl, 2-furyl and 2-pyridyl.
 37. The composition according to claim 1 wherein R₃ is selected from (CR₉R₁₀)_(n)R₈ wherein n is 1 to 6, R₉ and R₁₀ are independently selected from H, alkyl and aryl, and R₈ is selected from the group consisting of cycloalkyl, non-aromatic heterocyclic, CN, C₂R₅, CONR₅R₆, CONR₅R₆ and C(═NR₄)NR₅R₆.
 38. The composition according to claim 37 wherein n is 1 to 3, and R₉ and R₁₀ are selected from the group consisting of H and alkyl.
 39. The composition according to claim 37 wherein R₈ is CONR₅R₆, R₅ is hydrogen and R₆ is selected from the group consisting of unsubstituted alkyl and arylalkyl.
 40. The composition according to claim 1 wherein R₃ is CONR₅R₆, R₅ is H and R₆ is arylalkyl.
 41. The composition according to claim 1 wherein the compound is selected from the group: 7-(2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; N,N-bis(2-fluorobenzyl)-3-(2-fluorobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(2-fluorobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(3-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(3-aminobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; methyl 3-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)methylbenzoate; 3-(3,5-dimethoxybenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(5-chloro-2-thienyl)methyl-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; N-(3-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)methyl)phenyl-(1-methyl-1H-imidazol-4-yl)sulphonamide; 5-amino-N-benzyl-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylcarboxamide; 7-(2-furyl)-3-(3-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(2-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(2-aminobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; ethyl 5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylacetate; 3-(3cyanobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrmidine-5-amine; 7-(2-furyl)-3-(3-(3-pyridyl)propyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(3-trifluoromethylbenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(3-hydroxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(5-methyl-2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(2-fluorobenzyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(1H-pyrazol-3-yl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(2-fluorobenzyl)-7-(5-thiazolyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(3-methylbenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(3-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; (5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)acetic acid; 3-(3-chlorobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(2-fluorobenzyl)-7-(1H-pyrazol-3-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; (5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)acetamide; (5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-N-(3-chlorophenyl)acetamide; 7-(2-furyl)-3-(6-methoxy-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(2-thienylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(2-fluorobenzyl)-7-(2-thiazolyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(2-fluorobenzyl)-7-(2-thienyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(3-aminobenzyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(6-methyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(2-fluorobenzyl)-7-(5-methyl-2-thiazolyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; tert-butyl N-(3-(5-amino7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-ylmethyl)benzyl)carbamate; 3-(2,5-dimethoxybenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(2,6-difluorobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(2-fluorobenzyl)-7-(4-methyl-2-thiazolyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-thienyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 6-chloro-N-(7-(2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)pyridine-3-carboxamide; 3-(3-nitrobenzyl)-7-(5-thiazolyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(3-aminomethylbenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrmidine-5-amine; 3-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin3-ylmethyl)-N,N-dimethylbenzamide; 3-(3-aminobenzyl)-7-(2-thienyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)-N-methylbenzamide; 3-(3-aminobenzyl)-7-(5-thiazolyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(2-fluoro-5-methoxybenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; (5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-N-(2-pyridyl)acetamide; (5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-N-(2-pyridylmethyl)acetamide; (5-amino-7-(2-furyl)-3H-[ 1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-N-phenylacetamide; 3-(3,5-dinitrobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(5-methyl-2-furyl)-3-(3-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(2,3-difluorobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(2,4-difluorobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(5-methyl-2-furyl)-3-(6-methyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(2,6-difluorobenzyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrmidine-5-amine; 7-(5-methyl-2-furyl)-3-(2-thienylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(3-chlorobenzyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(4-methoxy-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(2-methylbenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(2,5-difluorobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(2-methoxy-5-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine; 3-(5-amino-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrmidine-3-ylmethyl)-N-methylbenzamide; N-(3-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)benzyl)acetamide; 3-(2-fluorobenzyl)-7-(5-oxazolyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(4-chloro-2-pyridylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrmidine-5-amine; 3-(6-fluoro-2-pyridylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(2-methoxybenzyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; tert-butyl N-(3-(5-amino-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-ylmethyl)benzyl)carbamate; 3-(2-aminobenzyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine hydrochloride; 3-(3,5-diaminobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(3-aminomethylbenzyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine hydrochloride; 7-(2-furyl)-3-(2-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(2-fluoro-5-nitrobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(5-amino-2-fluorobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(2-fluorobenzyl)-7-(1H-triazolo4yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(6-chloro-2-pyridylmethyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(5-methyl-2-furyl)-3-(6-phenyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(3-aminobenzyl)-7-(2-thiazolyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(5-amino-2-fluorobenzyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine hydrochloride; N-(3-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)benzyl)-3-methylbenzamide; 7-(5-methyl-2-furyl)-3-(4-nitro-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(4-hydroxylamino-2-pyridylmethyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(2-methyl-3-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(3-amino-2-methylbenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(3-amino-4methylbenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 3-(3,5-dimethylisoxazol-4-ylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5amine; 7-(2-furyl)-3-(3-methyl-2-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-cyclohexylmethyl-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(3-methyl-4-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(3-methyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(5-methyl-2-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(4amino-3-methylbenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)benzoic acid; 3-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)benzamide; 7-(2-furyl)-3-(2-methylthiazol-4-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrmidine-5-amine; 3-(3-aminomethylbenzyl)-7-(1H-pyrazol-3-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)-N-isopropyl-N-methylbenzamide; 3-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)-N-isopropylbenzamide; 3-(2-amino-5-methylbenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(4-cyano-2-pyridylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(5-methyl-2-pyrazinylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(8-quinolinylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(2-phenylthiazol-4-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(4-methyl-2-thiazolyl)-3-(3-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(4-chloro-3-nitrobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(1,2,5-benzoxadiazol-5-yl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(6-methoxymethyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5amine; 3-benzyl-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(3-amino-4-chlorobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(4-nitro-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(4-hydroxylamino-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5amine; 7-(2-furyl)-3-(6methyl-4-nitro-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(4-hydroxylamino-6-methyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(4chloro-2-nitrobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(2-amino-4-chlorobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(4-cyanobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(3,4-dimethoxybenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine trifluoroacetate salt; 7-(5-methyl-2-furyl)-3-(3-methyl-4-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(4-amino-3-methylbenzyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(5-methyl-3-oxazolyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(3-methyl-4-pyridylmethyl)-3H-[1,2,3]triazolo[4,5)pyrimidine-5-amine; 3-(1,2,5-benzothiadiazol-4-ylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(2-pyrazinylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(4-fluoro-3-nitrobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(3-nitrobenzyl)-7-phenyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(4-methyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; tert-butyl N-(2-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-ylmethyl)-4-pyridylmethyl)carbamate; 7-(2-furyl)-3-(3-methoxy-4-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(4-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(6-ethyl-2-pyridylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(2-ethyl-4-pyridylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; tert-butyl 7-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-ylmethyl)indole-1-carboxylate; tert-butyl 4-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-ylmethyl)indole-1-carboxylate; 7-(2-furyl)-3-(4-indolylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; tert-butyl N-(4-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-ylmethyl)benzyl)carbamate; 3-(4aminobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo4,5-d]pyrimidine-5-amine; tert-butyl 5-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-ylmethyl)indole-1-carboxylate; tert-butyl N-(4-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrmidine-3-ylmethyl)-2-fluorophenyl)carbamate; 3-(4-aminomethylbenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(5-ethyl-2-furyl)-3-(3-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; tert-butyl 6-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-ylmethyl)indole-1-carboxylate; 3-(4-amino-3-fluorobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; tert-butyl (4-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-ylmethyl)-3,5-difluorophenyl)carbonate; 3-(2,6-difluoro-4-hydroxybenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(3-aminobenzyl)-7-(5-ethyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(3-aminobenzyl)-7-phenyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(6-indolylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(5-indolylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyriridine-5-amine; 7-(2-furyl)-3-(7-indolylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(5-fluoro-2-nitrobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(2,6-difluoro-4-methoxybenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; tert-butyl N-(2-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-ylmethyl)benzyl)carbamate; 3-(1H-benzotriazol-5-ylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d[pyrimidine-5-amine 7-(2-furyl)-3-(2-methoxy-4-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; N-(3-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-ylmethyl)phenylacetamide; 3-(2-amninomethylbenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(3-(N,N-dimethylamine)benzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5amine; 3-(4-difluoromethoxybenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(6-phthalimidomethyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine5-amine; 3-(3-amino-4-fluorobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(2,3dihydrobenzofuran-5-ylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(5-bromo-2-fluorobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(2,3,5-trifluorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(2-fluoro-5-iodobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(2-furylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(2-amino-5-fluorobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; tert-butyl (5-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-ylmethyl)-2-nitrophenyl)carbonate; 3-(4-amino-3-hydroxybenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(4-amino-3-fluorobenzyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(3-aminobenzyl)-7-(1H-pyrazol-3-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(3-hydroxy-4-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; N-(6-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)-2-pyridylmethyl)acetamide; N-(2-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)benzyl)acetamide; 7-(2-furyl)-3-(3-thienylmethyl)-3H-[1,2,3]triazolo(4,5-d]pyrimidine-5-amine; 3-(3-amino-2-methylbenzyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(3-methyl-2-thienyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(6-alkyloxymethyl-2-pyridylmethyl)-N,N-dialkyl-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(6-methoxymethyl-2-pyridylmethyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(4-aminobenzyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(6-alkyloxymethyl-2-pyridylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5amine; 3-(6-alkyloxymethyl-2-pyridylmethyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(3-isopropyl4-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(quinolin-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(4-(N-methylamino)benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 2-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-1-(6-methyl-2-pyridyl)propanone; 3-(3-aminobenzyl)-7-(1H-pyrrole-2-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(3-nitrobenzyl)-7-(2-pyridyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine; N-(4-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)phenyl)acetamide; 7-(2-furyl)-3-(4-nitro-2-(2-trimethylsilylethoxy)methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(3-ethyl-4-nitrobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(2-(2-thienylmethyl))-3H-[1,2,3]triazolo[4,5-d]pyrmidine-5-amine; 7-(2-furyl)-3-(6-isopropyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(1-(2H-tetrahyropyran-2-yl)indazol-5-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(4,6-diisopropyl-2-pyridylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(5-indazolylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(2-hydroxy-4-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(6-vinyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; tert-butyl 5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-carboxylate; tert-butyl 3-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-ylmethyl)indole-1-carboxylate; 6-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-ylmethyl)pyridine-2-carboxaldehyde tert-butyl 2-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-ylmethyl)indole-1-caboxylate; 3-(2-indolylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrmidine-5-amine; 3-(5-ethyl-2-thienylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(3,4-methylenedioxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(4-amino-3-ethylbenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 2-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-1-phenylethanone; N-(3-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-methyl)phenyl)thiophene-2-carboxamide; 7-(2-furyl)-3-(6-hydroxymethyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine hydrochloride; N-(3-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-methyl)phenyl)-3,3-dimethylbutanamide; N-(3-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-methyl)phenyl)cyclopropanecarboxamide; 7-(2-furyl)-3-(6-n-propyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(6-isobutyloxymethyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(6-bromomethyl-2-pyridylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolol[4,5-d]pyrimidine-5-amine; 3-(4-amino-3-isopropylbenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(6-cyanomethyl-2-pyridylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(4-hydroxybenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 2-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-1-(4-nitrophenyl)ethanone; 4-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylacetyl)-benzonitrile; N-(3-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)phenyl)propanesulphonamide; N-(3-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)phenyl)-5-chloro-2-thiophenesuiphonamide; 7-(2-furyl)-3-(6-(N-methylamino)methyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine hydrochloride; 2-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-l -(4-(N,N-diethylamino)phenyl)ethanone; 7-(2-furyl)-3-(6-isopropyl-3-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 2-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-1-(4-methoxyphenyl)ethanone; tert-butyl 7-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-ylmethyl)-5-chloroindole-1-carboxylate; 3-(5-chloro-7-indolyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; N-(3-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)phenyl)-3,5-dimethylisoxazol-4-ylsulphonamide; 3-(6-(N,N-dimethylamino)methyl-2-pyridylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d ]pyrimidine-5-amine; 7-(2-furyl)-3-(6-methylthiomethyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 2-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-1-(2-nitrophenyl)ethanone; N-(3-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)phenyl)-1,2-dimethyl-1H-imidazol-4-ylsulphonamide; N,N-bis(6-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)-2-pyridylmethyl) methanesulphonamide; 7-(2-furyl)-3-(6-methylsulphonylmethyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; N-(6-(5-amino-7-(2-furyl)-3H-[1,2,3 ]triazolo[4,5-d]pyrimidin-3-ylmethyl)-2-pyridylmethyl)-N-methyl methanesulphonamide; 3-(3-aminobenzyl)-7-(4,5-dimethyl-2-thiazolyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(4-amino-2-fluorobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 2-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-1-indanone; 7-(2-furyl)-3-(5-methyl-7-indolylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; N-(4-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)-2-methylphenyl)formamide; 2-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-1-phenylpropanone; 3-(7-fluoro-5-indolyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(6-isopropoxymethyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(6-ethyl-2-pyridylmethyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(4-chloro-5-indolyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(7-bromo-5-indolyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(6-chloro-5-indolyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(3-(4-fluorobenzylamino)benzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(6-ethoxy-2-pyridylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(6-ethoxy-2-pyridylmethyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo]4,5-d]pyrimidine-5-amine; 3-(3-(2-pyridylmethylamino)benzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(1-(4-trifluoromethylphenyl)ethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(6-fluoro-5-indolyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(5-fluoro-2-indolyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(3,5-dimethyl-4-nitrobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(1-(3-fluorophenyl)ethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(7-chloro-5-indolyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(4-amino-3,5-dimethylbenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine 3-(1-(3-aminophenyl)ethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(6-(2-methoxyethyl)-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(1-(5,6-dimethyl-2-pyridyl)propyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(3-nitrobenzyl)-7-(1H-pyrazol-3-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine hydrochloride; 7-(5-methyl-2-furyl)-3-(2-methyl-3-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(5-methyl-2-furyl)-3-(4-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; tert-butyl N-(4-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-ylmethyl)phenyl)-N-methylcarbamate; tert-butyl 2-(5-amino-3-(3-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)pyrrole-1-carboxylate; 7-(4,5-dimethylthiazol-2-yl)-3-(3-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(2-fluoro-4-nitrobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; tert-butyl 7-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-ylmethyl)-5-methylindole-1-carboxylate, and ethyl N-(4-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)methyl)-2-methylphenyl)carbamate.
 42. The composition according to claim 1 wherein the compound is selected from the group consisting of: 3-(2-fluorobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(3-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(3-aminobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(3-aminobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(3-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 7-(2-furyl)-3-(2-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; 3-(2-aminobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine; and 3-(3-cyanobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine.
 43. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein R₁ is selected from the group consisting of H, alkyl, aryl, alkoxy, aryloxy, alkylthio, arylthio, halogen, CN, NR₅R₆, NR₄COR₅, NR₄CONR₅R₆, NR₄CO₂R₇ and NR₄SO₂R₇; R₂ is an aryl attached via an unsaturated ring carbon of said aryl group; R₃ is selected from the group consisting of H, an alkyl, COR₅, CO₂R₇, CONR₅R₆, CONR₄NR₅R₆ and SO₂R₇; R₄, R₅ and R₆ are independently selected from the group consisting of H, alkyl and aryl, or where R₅ and R₆ are in an NR₅R₆ group, R₅ and R₆ may be linked to form a heterocyclic group, or where R₄, R₅ and R₆ are in a (CONR₄NR₅R₆) group, R₄ and R₅ may be linked to form a heterocyclic group; and R₇ is selected from the group consisting of alkyl and aryl, provided that when R₃ is methyl, R₁ is not H.
 44. The compound according to claim 43, wherein R₃ is not methyl.
 45. The compound according to claim 43, wherein R₁ is NR₅R₆; R₂ is an N, O or S-containing heteroaryl group; and R₃ is an alkyl substituted by aryl.
 46. The compound according to claim 43, wherein R₁ is NH₂; R₂ is 2-furyl; R₃ is (CR₉R₁₀)_(n)R₁₁ wherein n is 1 to 6, R₉ and R₁₀ are independently selected from H, alkyl and aryl, and R₁₁ is a substituted aryl or heteroaryl group.
 47. The compound of claim 43 wherein the compound of formula (I) is 3-(4-amino-3-methylbenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo [4,5-d]pyrimidine-5-amine, or a pharmaceutically acceptable salt thereof.
 48. The composition of claim 1 wherein the compound of formula (I) is 3-(4-amino-3-methylbenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine, or a pharmaceutically acceptable salt thereof. 